David L Bartlett

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Are you David L Bartlett?

Claim your profile

Publications (209)990.16 Total impact

  • [show abstract] [hide abstract]
    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
  • [show abstract] [hide abstract]
    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
  • [show abstract] [hide abstract]
    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
  • [show abstract] [hide abstract]
    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
  • [show abstract] [hide abstract]
    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
  • Source
    [show abstract] [hide abstract]
    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
  • Source
    [show abstract] [hide abstract]
    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.
  • [show abstract] [hide abstract]
    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
  • Source
    [show abstract] [hide abstract]
    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
  • [show abstract] [hide abstract]
    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
  • [show abstract] [hide abstract]
    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
  • Source
    [show abstract] [hide abstract]
    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
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The effective accumulation and interaction of mature dendritic cells (DCs) and naïve T cells within lymph nodes (LNs), which are driven by the CCR7-CCL19/CCL21 chemokine axis, are critical for the induction of adaptive T-cell immunity. Human natural killer (NK) cells activated by interleukin (IL)-18 exhibit a unique 'helper' activity in promoting productive DC-T cell interactions, inducing DC maturation and shifting DC-primed T-cell responses toward a TH1 polarization. Here, we demonstrate that such IL-18-activated 'helper' NK cells uniquely stimulate DCs to produce high levels of CCL19 through tumor necrosis factor α (TNFα) and interferon γ (IFNγ), a process that relies on secondary NK-cell activation by additional inflammatory signals including IFNα, IL-15, IL-12 and IL-2. DCs activated by helper NK cells not only promote the efficient CCR7-mediated recruitment of naïve CD8(+) T cells, but also stimulate their expansion and expression of granzyme B. Using an ex vivo explant culture system based on LNs isolated from colorectal cancer patients, we found that CCL19 is upregulated in human tumor-associated lymphoid tissues treated with helper NK cell-stimulating factors. Our findings demonstrate the ability of 2 signal-activated helper NK cells to promote the production of the DC- and naïve/memory T cell-attracting chemokine CCL19 in LNs, and provide a rationale for the therapeutic application of IL-18-containing 'combinatorial adjuvants' to facilitate the induction of antitumor immune responses.
    Oncoimmunology. 09/2013; 2(9):e26245.
  • [show abstract] [hide abstract]
    ABSTRACT: Computer-assisted robotic surgery allows complex resections and anastomotic reconstructions to be performed with nearly identical standards to open surgery. We applied this technology to a variety of pancreatic resections to assess the safety, feasibility, versatility, and reliability of this technology. A retrospective review of a prospective database of robotic pancreatic resections at a single institution between August 2008 and November 2012 was performed. Perioperative outcomes were analyzed. A total of 250 consecutive robotic pancreatic resections were analyzed; pancreaticoduodenectomy (132), distal pancreatectomy (83), central pancreatectomy (13), pancreatic enucleation (10), total pancreatectomy (5), Appleby resection (4), and Frey procedure (3). Thirty-day and 90-day mortality was 0.8% and 2.0%. Rate of Clavien 3 and 4 complications was 14% and 6%. The International Study Group on Pancreatic Fistula grade C fistula rate was 4%. Mean operative time for the 2 most common procedures was 529 ± 103 minutes for pancreaticoduodenectomy and 257 ± 93 minutes for distal pancreatectomy. Continuous improvement in operative times was observed over the course of the experience. Conversion to open procedure was required in 16 patients (6%) (11 with pancreaticoduodenectomy, 2 with distal pancreatectomy, 2 with central pancreatectomy, 1 with total pancreatectomy) for failure to progress (14) and bleeding (2). This represents to our knowledge the largest series of robotic pancreatic resections. Safety and feasibility metrics including the low incidence of conversion support the robustness of this platform and suggest no unanticipated risks inherent to this new technology. By defining these early outcome metrics, this report begins to establish a framework for comparative effectiveness studies of this platform.
    Annals of surgery 08/2013; · 7.90 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Eighty percent of patients with resected pancreatic ductal carcinoma (PDC) experience treatment failure within 2 years. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with the angiogenesis inhibitor bevacizumab (BEV) and accelerated 30 Gy radiotherapy (RT) would improve outcomes among patients with potentially resectable PDC. This phase II trial tested induction FDR GEM (1,500 mg/m(2)) plus BEV (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin. Subjects underwent laparoscopy and resection after day 85. Therapy was considered effective if the complete pathologic response rate exceeded 10 % and the margin-negative resection rate exceeded 80 %. Fifty-nine subjects were enrolled; 29 had potential portal vein involvement. Two grade 4 (3.4 %) and 19 grade 3 toxicities (32.8 %) occurred. Four subjects manifested radiographic progression, and 10 had undetected carcinomatosis. Forty-three pancreatic resections (73 %) were performed, including 19 portal vein resections (44 %). Margin-negative outcomes were observed in 38 (88 %, 95 % confidence interval [CI] 75-96), with one complete pathologic response (2.3 %; 95 % CI 0.1-12). There were seven (6 grade 3; 1 grade 4) wound complications (13 %). Median overall survival for the entire cohort was 16.8 months (95 % CI 14.9-21.3) and 19.7 months (95 % CI 16.5-28.2) after resection. Induction therapy with FDR GEM and BEV, followed by accelerated BEV/RT to 30 Gy, was well tolerated. Although both effectiveness criteria were achieved, survival outcomes were equivalent to published regimens.
    Annals of Surgical Oncology 08/2013; · 4.12 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The purpose of this study was to describe a single-institution experience with adrenal metastasectomy and to elucidate factors that may bear prognostic significance. This is a single-center, retrospective review of patients with adrenal metastasis who underwent adrenalectomy performed with curative intent between 2000 and 2012. The Kaplan-Meier method was used to evaluate overall survival from time of adrenalectomy to death or last follow-up. Primary endpoint was death from any cause. Clinical variables were examined for association with survival. The study included 62 patients with mean age of 60 (±12) years; 55 % (34 of 62) were male, 85 % (53 of 62) presented with isolated adrenal metastasis, and 82 % (51 of 62) had metachronous disease with median disease-free interval (DFI) of 22 months (range, 6-217 months). Non-small cell lung cancer (NSCLC) was the most common primary comprising 50 % of cases. Median survival for the study population was 30 months (range, 1-145 months) and 5-year survival was 31 %. Patients with NSCLC had significantly shortened survival compared with non-NSCLC with median and 5-year survival of 17 versus 47 months and 27 % versus 38 %, respectively (p = .033). Synchronous metastasis (p = .028) and DFI < 12 months (p = .038) were also associated with worse survival outcome, though male gender (p = .69) and oligometastatic disease (p = .62) were not. Adrenal metastasectomy resulted in median survival of 30 months and 5-year survival of 31 %. Shorter survival was associated with lung primary, short disease-free interval, and synchronous metastasis, but not with the presence of oligometastatic disease provided that the primary cancer and additional metastatic lesions were adequately controlled and amenable to resection.
    Annals of Surgical Oncology 06/2013; · 4.12 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.
    Annals of Surgical Oncology 06/2013; · 4.12 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Genetically engineered tumor-selective vaccinia virus (VV) has been demonstrated to be a highly effective oncolytic agent, but immune clearance may limit its therapeutic potential. As previously demonstrated, immunosuppression can lead to significant enhancement of viral recovery and therapeutic effect, but the magnitude of complement-mediated viral inactivation has not been fully elucidated and warrants further investigation. Using fluorescent microscopy and quantitative plaque assays, we have determined complement's key role in viral clearance and its multi-faceted means to pathogen destruction. Complement can lead to direct viral destruction and inhibition of viral uptake into cells, even in the absence of anti-vaccinia antibodies. Our data demonstrate C5 to be integral to the clearance pathway, and its inhibition by Staphylococcal superantigen-like protein leads to a 90-fold and 150-fold enhancement of VV infectivity in both the presence and absence of anti-VV antibodies, respectively. This study suggests that complement inhibition may reduce vaccinia viral neutralization and may be critical to future in vivo work.Cancer Gene Therapy advance online publication, 10 May 2013; doi:10.1038/cgt.2013.26.
    Cancer gene therapy 05/2013; · 3.13 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Cancer vaccines, to date, have shown limited effect to control the growth of established tumors due largely to effector failure of the antitumor immune responses. Tumor lesion is characterized as chronic indolent inflammation in which the effector function of tumor-infiltrating lymphocytes (TILs) is severely impaired. In this study, we investigated whether the effector function of CD8 TILs could be rescued by converting the chronic inflammation milieu to acute inflammation within tumors. We found that injection of TLR3/9 ligands (polyI:C/CpG) into a tumor during the effector phase of lentivector (lv) immunization effectively rescued the function of lv-activated CD8 TILs and decreased the percentage of T regulatory within the tumor, resulting in a marked improvement in the antitumor efficacy of lv immunization. Mechanistically, rescue of the effector function of CD8 TILs by TLR3/9 ligands is most likely dependent on production, within a tumor, of type-1 IFN that can mature and activate tumor-infiltrating dendritic cells. The effector function of CD8 TILs could not be rescued in mice lacking intact type I IFN signaling. These findings have important implications for tumor immunotherapy, suggesting that type I IFN-mediated activation of tumor-infiltrating dendritic cells within a tumor will most likely restore/enhance the effector function of CD8 TILs and thus improve the antitumor efficacy of current cancer vaccines.
    The Journal of Immunology 04/2013; · 5.52 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: BACKGROUND: The majority of patients with periampullary cancer develop local or metastatic recurrence despite successful negative margin resection. Unfortunately, there are no established therapeutic strategies for managing these patients. The literature on the surgical resection of recurrent disease is limited. METHODS: This is a retrospective study evaluating patients who underwent reoperative resection of recurrent periampullary cancer at a single institution between 1990 and 2011. Perioperative outcomes were compared with those of the original primary resections for patients with local recurrence. Kaplan-Meier curves were used to evaluate survival. RESULTS: Twenty-two patients underwent reoperative resection following the successful primary resection of periampullary cancers. Median survival from the time of reoperation was 28.1 months. A greater survival benefit was seen in patients undergoing reoperative resection with >15 months between the primary resection and recurrence (40.6 months versus 8.2 months; P < 0.05). Complication rates were lower after reoperative resection compared with the primary resection (20% versus 70%). Perioperative characteristics including operative time, estimated blood loss and hospital stay were similar in both the primary and reoperation procedures. CONCLUSIONS: Surgical resection of periampullary cancer recurrence is feasible, safe and may offer survival benefits in comparison with alternative treatment modalities. Reoperative resection should be considered, especially in patients in whom the time to recurrence is lengthy.
    HPB 04/2013; · 1.94 Impact Factor

Publication Stats

4k Citations
990.16 Total Impact Points

Institutions

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