David L Bartlett

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (216)1012.6 Total impact

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    ABSTRACT: Single-incision right colectomy has emerged as a safe and feasible alternative to standard laparoscopic resection. As with any new surgical approach, definition of the number of procedures required to optimize the technique is an important goal. Data on this learning curve for single-incision right colectomy are lacking; therefore, we report the outcomes of consecutive single-incision right colectomies to identify the procedural learning curve.
    Surgical endoscopy. 08/2014;
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    ABSTRACT: In this study, we attempted to develop a multimodality approach using chemotherapeutic agent mitomycin C, biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat colon cancer. For this study, human colon cancer LS174T, LS180, HCT116 and CX-1 cells were infected with secretory TRAIL-armed adenovirus (Ad.TRAIL) and treated with chemotherapeutic agent mitomycin C and hyperthermia. The combinatorial treatment caused a synergistic induction of apoptosis which was mediated through an increase in caspase activation. The combinational treatment promoted the JNK-Bcl-xL-Bak pathway which transmitted the synergistic effect through the mitochondria-dependent apoptotic pathway. JNK signaling led to Bcl-xL phosphorylation at serine 62, dissociation of Bak from Bcl-xL, oligomerization of Bak, alteration of mitochondrial membrane potential, and subsequent cytochrome c release. Overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed the synergistic death effect. Interestingly, Beclin-1 was dissociated from Bcl-xL and overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed dissociation of Beclin-1 from Bcl-xL. A combinatorial treatment of mitomycin C, Ad.TRAIL and hyperthermia induced Beclin-1 cleavage, but the Beclin-1 cleavage was abolished in Beclin-1 double mutant (D133A/D146A) knock-in HCT116 cells, suppressing the apoptosis induced by the combination therapy. We believe that this study supports the application of the multimodality approach to colon cancer therapy.
    Apoptosis : an international journal on programmed cell death. 08/2014;
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    ABSTRACT: Baseline carbohydrate antigen 19-9 (CA 19-9) is a useful prognostic marker in pancreatic ductal adenocarcinoma (PDA); however, data on the significance of a change in CA 19-9 following neoadjuvant therapy are lacking.
    Annals of Surgical Oncology 08/2014; · 4.12 Impact Factor
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    ABSTRACT: Inflammation plays a central role in peritoneal carcinomatosis (PC) etiology and progression, and circulating levels of inflammatory biomarkers prior to surgery predict progression-free and overall survival in PC patients. Depression and fatigue are prevalent among PC patients, and experimental research shows that these symptoms may be mediated by proinflammatory cytokines. As yet unstudied is the possibility that the heightened levels of inflammatory markers in PC patients may contribute to their experience of common neurovegetative symptoms.
    Brain Behavior and Immunity 07/2014; · 5.61 Impact Factor
  • Z S Guo, D L Bartlett
    Cancer gene therapy. 07/2014; 21(7):261-3.
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    ABSTRACT: Obesity has been described as a risk factor for surgical complications and may play a prominent role in the progression, recurrence, and survival rates of various cancers. Our objective was to investigate the impact of being overweight or obese on perioperative and oncologic outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) from mucinous appendiceal neoplasms (MAN).
    Annals of Surgical Oncology 06/2014; · 4.12 Impact Factor
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    ABSTRACT: Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2-6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7-14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.Modern Pathology advance online publication, 14 March 2014; doi:10.1038/modpathol.2014.37.
    Modern Pathology 03/2014; · 5.25 Impact Factor
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    ABSTRACT: Recent studies indicate that a complex relationship exists between autophagy and apoptosis. In this study we investigated a regulatory relationship between autophagy and apoptosis in colorectal cancer cells utilizing molecular and biochemical approaches. For this study, human colorectal carcinoma HCT116 and CX-1 cells were treated with two chemotherapeutic agents-oxaliplatin, which induces apoptosis, and bortezomib, which triggers both apoptosis and autophagy. A combinatorial treatment of oxaliplatin and bortezomib caused a synergistic induction of apoptosis which was mediated through an increase in caspase activation. The combinational treatment of oxaliplatin and bortezomib promoted the JNK-Bcl-xL-Bax pathway which modulated the synergistic effect through the mitochondria-dependent apoptotic pathway. JNK signaling led to Bcl-xL phosphorylation at serine 62, oligomerization of Bax, alteration of mitochondrial membrane potential, and subsequent cytochrome c release. Overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed cytochrome c release and synergistic death effect. Interestingly, Bcl-xL also affected autophagy through alteration of interaction with Beclin-1. Beclin-1 was dissociated from Bcl-xL and initiated autophagy during treatment with oxaliplatin and bortezomib. However, activated caspase 8 cleaved Beclin-1 and suppressed Beclin-1-associated autophagy and enhanced apoptosis. A combinatorial treatment of oxaliplatin and bortezomib-induced Beclin-1 cleavage was abolished in Beclin-1 double mutant (D133AA/D149A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. In addition, the combinatorial treatment significantly inhibited colorectal cancer xenografts' tumor growth. An understanding of the molecular mechanisms of crosstalk between apoptosis and autophagy will support the application of combinatorial treatment to colorectal cancer.
    Biochemical pharmacology 01/2014; · 4.25 Impact Factor
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    ABSTRACT: We analyzed a series of 55 disseminated appendiceal mucinous neoplasms treated at our institution for GNAS and KRAS mutations in an attempt to correlate mutation status with clinicopathologic findings and patient survival. GNAS mutations (p.R201H, c.602G > A and p.R201C, c.602C > T) were identified in 17/55 (31%) of disseminated mucinous neoplasms and were found in 8/23 (35%) low-grade mucinous neoplasms, 7/19 (37%) high-grade mucinous adenocarcinomas lacking a signet ring cell component, and 2/13 (15%) high-grade mucinous adenocarcinomas with a signet ring cell component. All seven mucinous adenocarcinomas composed of pure (>95%) signet ring cells harbored wild-type GNAS. There was no significant association between GNAS mutations and gender and age (both with p > 0.05) or between GNAS mutations and individual adverse histologic features including cytologic grade, destructive invasion, tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cells (all with p > 0.05). KRAS mutations were identified in 22/55 (40%) disseminated mucinous neoplasms. GNAS-mutated disseminated appendiceal mucinous neoplasms more frequently harbored concurrent KRAS mutations compared with GNAS-wild-type tumors (65% vs. 29%, p = 0.018). GNAS mutations were not significantly associated with overall survival (both with p > 0.05). Only overall tumor grade was an independent predictor of overall survival in the multivariable analysis (p = 0.01). Our results indicate that GNAS mutations are frequently identified in both low-grade and high-grade disseminated appendiceal mucinous neoplasms indicating that GNAS mutation status cannot be used to distinguish between low-grade from high-grade appendiceal mucinous neoplasms.
    Human pathology 01/2014; · 3.03 Impact Factor
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    Zong Sheng Guo, Zuqiang Liu, David L Bartlett
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    ABSTRACT: Oncolytic viruses (OVs) are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD), including immunogenic apoptosis, necrosis/necroptosis, pyroptosis, and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high-mobility group box 1, uric acid, and other damage-associated molecular patterns as well as pathogen-associated molecular patterns as danger signals, along with tumor-associated antigens, to activate dendritic cells and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis, or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells toward certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity, and thus the overall therapeutic efficacy.
    Frontiers in Oncology 01/2014; 4:74.
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    ABSTRACT: & Aims: High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice following induction of acute pancreatitis. We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1flox/flox mice). Acute pancreatitis was induced in these mice (HMGB1flox/flox mice served as controls) following injection of L-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. Following injection of L-arginine or cerulein, Pdx1-Cre; HMGB1flox/flox mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1flox/flox mice following L-arginine- or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA Nfκb, degradation of Iκb, and phosphorylation of Mapk. Inhibitors of reactive oxygen species (N-acetyl-L-cysteine) blocked L-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of Nfκb in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1flox/flox and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival following L-arginine injection. In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage.
    Gastroenterology 12/2013; · 12.82 Impact Factor
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    ABSTRACT: Most patients with malignant peritoneal mesothelioma (MPM) present with late-stage, unresectable disease that responds poorly to systemic chemotherapy while, at the same time, effective targeted therapies are lacking. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in MPM. We prospectively analyzed 65 patients with MPM undergoing CRS/HIPEC between 2001 and 2010. Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. Adequate CRS was achieved in 56 patients (CC-0 = 35; CC-1 = 21), and median simplified peritoneal cancer index (SPCI) was 12. Pathologic assessment revealed predominantly epithelioid histology (81 %) and biphasic histology (8 %), while lymph node involvement was uncommon (8 %). Major postoperative morbidity (grade III/IV) occurred in 23 patients (35 %), and 60-day mortality rate was 6 %. With median follow-up of 37 months, median overall survival was 46.2 months, with 1-, 2-, and 5-year overall survival probability of 77, 57, and 39 %, respectively. Median progression-free survival was 13.9 months, with 1-, 2-, and 5-year disease failure probability of 47, 68, and 83 %, respectively. In a multivariate Cox-regression model, age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), aggressive histology (epithelioid, biphasic), and postoperative sepsis were joint significant predictors of poor survival (chi square = 42.8; p = 0.00001), while age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), and aggressive histology (epithelioid, biphasic) were joint significant predictors of disease progression (Chi square = 30.6; p = 0.00001). Tumor histology, disease burden, and the ability to achieve adequate surgical cytoreduction are essential prognostic factors in MPM patients undergoing CRS/HIPEC.
    Annals of Surgical Oncology 12/2013; · 4.12 Impact Factor
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    ABSTRACT: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) of colorectal origin increases survival (OS) compared to systemic chemotherapy alone. Signet ring histology demonstrates aggressive behavior with poor survival. We sought to determine whether CRS/HIPEC increases survival in this subset of patients. We reviewed 67 patients with PC of appendiceal (AP, n = 37) or colorectal origin (CRC, n = 30) with signet cell histology from a prospective database between May 2001 and August 2011. Survival analysis and multivariate Cox regression were used to determine prognostic factors for survival. Complete CRS (CC-0/1) was achieved in 77 % (CRC) and 73 % (AP) of patients. Progression-free survival (PFS) and OS were 9 and 12 months in CRC and 12 and 21 months in AP patients. In the CRC group, univariate predictors of poor survival included female gender, age, American Society of Anesthesiologists score, preoperative albumin, completeness of cytoreduction, and morbidity. In a multivariate Cox regression model, incomplete cytoreduction (CC-2/3) and female gender were joint significant predictors of poor survival. In the AP group, significant univariate predictors of poor survival included higher EBL and PCI score. In a multivariate Cox regression model, blood loss of >500 ml and a body mass index of <25 kg/m(2) were joint significant predictors of poor survival. AP signet cell tumors demonstrate a more favorable outcome than CRC signet cell tumors after CRC/HIPEC for carcinomatosis, suggesting an underlying difference in biology. CRS/HIPEC does not confer survival benefit in colorectal signet ring carcinomatosis unless complete cytoreduction can be achieved, whereas appendiceal signet ring carcinomatosis may benefit, regardless of resectability.
    Annals of Surgical Oncology 11/2013; · 4.12 Impact Factor
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    ABSTRACT: Peritoneal carcinomatosis from gastric cancer (GPC) responds poorly to systemic chemotherapy. Limited published data demonstrate improved outcomes after aggressive locoregional therapies. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in GPC. We prospectively analyzed 23 patients with GPC undergoing CRS/HIPEC between 2001 and 2010. Kaplan-Meier survival curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes. CRS/HIPEC was performed for synchronous GPC in 20 patients and metachronous GPC in 3 patients. Adequate CRS was achieved in 22 patients (CC-0 = 17; CC-1 = 5) and median peritoneal cancer index was 10.5. Most patients received preoperative chemotherapy (83 %) and total gastrectomy (78 %). Pathology revealed diffuse histology (65 %), signet cells (65 %) and LN involvement (64 %). Major postoperative morbidity occurred in 12 patients, with 1 in-hospital mortality at postoperative day 66. With median follow-up of 52 months, median overall survival (OS) was 9.5 months (95 % confidence interval 4.7-17.3), with 1- and 3- year OS rates of 50 and 18 %. Median progression-free survival (PFS) was 6.8 months (95 % confidence interval 3.9-14.6). In a multivariate Cox regression model, male gender [hazard ratio (HR) 6.3], LN involvement (HR 1.2), residual tumor nodules (HR 2.4), and >2 anastomoses (HR 2.8) were joint significant predictors of poor OS (χ (2) = 18.2, p = 0.001), while signet cells (HR 8.9), anastomoses >2 (HR 5.5), and male gender (HR 2.4) were joint significant predictors of poor progression (χ (2) = 16.3, p = 0.001). Aggressive CRS/HIPEC for GPC may confer a survival benefit in select patients with limited lymph node involvement and completely resectable disease requiring less extensive visceral resections.
    Annals of Surgical Oncology 11/2013; · 4.12 Impact Factor
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    ABSTRACT: Background. Cytoreductive surgery (CRS) and hyper-thermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) of colorectal origin increases survival (OS) compared to systemic chemother-apy alone. Signet ring histology demonstrates aggressive behavior with poor survival. We sought to determine whether CRS/HIPEC increases survival in this subset of patients. Methods. We reviewed 67 patients with PC of appendic-eal (AP, n = 37) or colorectal origin (CRC, n = 30) with signet cell histology from a prospective database between May 2001 and August 2011. Survival analysis and multi-variate Cox regression were used to determine prognostic factors for survival. Results. Complete CRS (CC-0/1) was achieved in 77 % (CRC) and 73 % (AP) of patients. Progression-free sur-vival (PFS) and OS were 9 and 12 months in CRC and 12 and 21 months in AP patients. In the CRC group, univar-iate predictors of poor survival included female gender, age, American Society of Anesthesiologists score, preop-erative albumin, completeness of cytoreduction, and morbidity. In a multivariate Cox regression model, incomplete cytoreduction (CC-2/3) and female gender were joint significant predictors of poor survival. In the AP group, significant univariate predictors of poor survival included higher EBL and PCI score. In a multivariate Cox regression model, blood loss of [500 ml and a body mass index of \25 kg/m 2 were joint significant predictors of poor survival. Conclusions. AP signet cell tumors demonstrate a more favorable outcome than CRC signet cell tumors after CRC/ HIPEC for carcinomatosis, suggesting an underlying dif-ference in biology. CRS/HIPEC does not confer survival benefit in colorectal signet ring carcinomatosis unless complete cytoreduction can be achieved, whereas appen-diceal signet ring carcinomatosis may benefit, regardless of resectability.
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    ABSTRACT: To evaluate outcomes of isolated hepatic perfusion (IHP) on isolated liver metastases (LMs). Isolated unresectable LMs are often the main determinant of overall survival (OS) for colorectal cancer (CRC) and other solid malignancies. We hypothesized that IHP can be performed safely and yield impressive responses for a variety of solid tumor pathology, using different perfusion agents. Retrospective review of a prospectively collected database of patients undergoing IHP for unresectable solid tumor LM. Between 2003 and 2012, IHP was completed in 91 patients. Primary tumor pathology was CRC = 54, non-CRC = 37 (ocular/cutaneous melanoma = 32, cholangiocarcinoma = 3, appendiceal = 1, and breast = 1). IHP employed Melphalan (n = 69) (CRC = 32, non-CRC = 37), Oxaliplatin (n = 10) (CRC), or Oxaliplatin + 5FU (n = 12) (CRC). Hepatic arterial infusion (HAI) pumps were placed in all CRC patients. There were 3(3.3%) perioperative deaths. Response rates for CRC, melanoma, and cholangiocarcinoma were 68.2%, 57.1%, and 100% respectively. Response rates for CRC patients using 5FU + Oxaliplatin, Oxaliplatin, or Melphalan were 83.3%, 66.7%, and 60.9%, respectively. Median OS for the CRC patients (from IHP date) was 23 months (95% confidence interval: 15-28 months). On univariate analysis, receipt of HAI-FUDR (floxuridine) within 1 year of IHP was the only factor associated with improved OS (P = 0.043) in CRC patients. IHP results in excellent response rates for patients with unresectable liver metastasis from solid tumors. Improved local control for CRC patients undergoing IHP-HAI may improve survival.
    Annals of surgery 10/2013; · 7.90 Impact Factor
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    ABSTRACT: Oncolytic vaccinia virus (VV) therapy has shown promise in preclinical models and in clinical studies. However, complete responses, have rarely been observed. This lack of efficacy is most likely due to suboptimal virus spread through the tumor resulting in limited tumor cell destruction. We reasoned that redirecting T cells to the tumor has the potential to improve the anti-tumor activity of oncolytic VVs. We therefore constructed a VV encoding a secretory bi-specific T-cell engager consisting of 2 single chain variable fragments specific for CD3 and the tumor cell surface antigen EphA2 (EphA2-T-cell engager armed VV; EphA2-TEA-VV). In vitro, EphA2-TEA-VV's ability to replicate and induce oncolysis was similar to that of unmodified virus. However, only tumor cells infected with EphA2-TEA-VV induced T-cell activation as judged by the secretion of IFNγ and IL-2. In coculture assays EphA2-TEA-VV not only killed infected tumor cells, but in the presence of T cells also induced bystander killing of non-infected tumor cells. In vivo, EphA2-TEA-VV plus T cells had potent antitumor activity in comparison to control VV plus T cells in a lung cancer xenograft model. Thus, arming oncolytic VVs with T-cell engagers may represent a promising approach to improve oncolytic virus therapy.Molecular Therapy (2013); doi:10.1038/mt.2013.240.
    Molecular Therapy 10/2013; · 7.04 Impact Factor
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    ABSTRACT: Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared-self/tumor antigens that are only able to induce weak immune responses. In this study, we investigated whether the HCC-associated self/tumor antigen of alpha-fetoprotein (AFP) could be engineered to create an effective vaccine to break immune tolerance and potently activate CD8 T cells to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. We found that the approach of computer-guided methodical epitope-optimization created a highly immunogenic AFP and that immunization with lentivector expressing the epitope-optimized AFP, but not wild-type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only cross-recognized short synthetic wild-type AFP peptides, but also recognized and killed tumor cells expressing wild-type AFP protein. Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. In addition, prime-boost immunization with the optimized AFP significantly increased the frequency of AFP-specific memory CD8 T cells in the liver that were highly effective against emerging HCC tumor cells, further enhancing the tumor prevention of carcinogen-induced autochthonous HCC. Our data demonstrate that epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. Our study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild-type AFP. (Hepatology 2013;).
    Hepatology 10/2013; · 12.00 Impact Factor
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    ABSTRACT: To perform a matched comparison of surgical and postsurgical outcomes between our robotic and laparoscopic hepatic resection experience. The application of robotic technology and technique to liver surgery has grown. Robotic methods may have the potential to overcome certain laparoscopic disadvantages, but few studies have drawn a matched comparison of outcomes between robotic and laparoscopic liver resections. Demographics, intraoperative variables, and postoperative outcomes among patients undergoing robotic (n = 57) and laparoscopic (n = 114) hepatic resections between November 2007 and December 2011 were reviewed. A 1:2 matched analysis was performed by individually matching patients in the robotic cohort to patients in the laparoscopic cohort based on demographics, comorbidities, performance status, and extent of liver resection. Matched patients undergoing robotic and laparoscopic liver resections displayed no significant differences in operative and postoperative outcomes as measured by blood loss, transfusion rate, R0 negative margin rate, postoperative peak bilirubin, postoperative intensive care unit admission rate, length of stay, and 90-day mortality. Patients undergoing robotic liver surgery had significantly longer operative times (median: 253 vs 199 minutes) and overall room times (median: 342 vs 262 minutes) compared with their laparoscopic counterparts. However, the robotic approach allowed for an increased percentage of major hepatectomies to be performed in a purely minimally invasive fashion (81% vs 7.1%, P < 0.05). This is the largest series comparing robotic to laparoscopic liver resections. Robotic and laparoscopic liver resection display similar safety and feasibility for hepatectomies. Although a greater proportion of robotic cases were completed in a totally minimally invasive manner, there were no significant benefits over laparoscopic techniques in operative outcomes.
    Annals of surgery 09/2013; · 7.90 Impact Factor
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    ABSTRACT: Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines.
    Molecular Cancer 09/2013; 12(1):103. · 5.13 Impact Factor

Publication Stats

4k Citations
1,012.60 Total Impact Points

Institutions

  • 2003–2014
    • University of Pittsburgh
      • • Division of Surgical Oncology
      • • Department of Surgery
      Pittsburgh, Pennsylvania, United States
  • 2013
    • Loyola University Medical Center
      • Department of Surgery
      Maywood, IL, United States
    • University of Maryland Medical Center
      Baltimore, Maryland, United States
    • Georgia Regents University
      Augusta, Georgia, United States
  • 2012–2013
    • Medical College of Wisconsin
      • • Division of Surgical Oncology
      • • Department of Surgery
      Milwaukee, WI, United States
    • University of Florida
      Gainesville, Florida, United States
    • Krankenhaus Barmherzige Brüder Regensburg
      Ratisbon, Bavaria, Germany
  • 2011
    • Georgia Health Sciences University
      Augusta, Georgia, United States
    • Southern Medical University
      • Department of Immunology
      Guangzhou, Guangdong Sheng, China
  • 2010–2011
    • University of Maryland, Baltimore
      • Department of Surgery
      Baltimore, MD, United States
    • Stony Brook University
      • Department of Surgery
      Stony Brook, NY, United States
  • 1999–2011
    • National Cancer Institute (USA)
      • • Surgery Branch
      • • Center for Cancer Research
      Maryland, United States
    • Technische Universität München
      München, Bavaria, Germany
  • 2009
    • Yonsei University Hospital
      • Department of Internal Medicine
      Seoul, Seoul, South Korea
  • 2001–2009
    • NCI-Frederick
      Maryland, United States
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
    • Cancer Research and Biostatistics
      Seattle, Washington, United States
  • 1996–2009
    • National Institutes of Health
      • • Branch of Surgery
      • • Section on Human Iron Metabolism
      Maryland, United States
    • University of Pennsylvania
      • Department of Surgery
      Philadelphia, Pennsylvania, United States
  • 2008
    • Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)
      • Department of Radiology
      Palermo, Sicily, Italy
  • 2004
    • UPMC
      Pittsburgh, Pennsylvania, United States
    • University of Toronto
      Toronto, Ontario, Canada