David L Bartlett

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (243)1154.97 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: It is well known that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis can be initially triggered by surface death receptors (the extrinsic pathway) and subsequently amplified through mitochondrial dysfunction (the intrinsic pathway). However, little is known about signaling pathways activated by the TRAIL-induced endoplasmic reticulum (ER) stress response. In this study, we report that TRAIL-induced apoptosis is associated with the endoplasmic reticulum (ER) stress response. Human colorectal carcinoma HCT116 cells were treated with TRAIL and the ER stress-induced signal transduction pathway was investigated. During TRAIL treatment, expression of ER stress marker genes, in particular the BiP (binding immunoglobulin protein) gene, was increased and activation of the PERK (PKR-like ER kinase)-eIF2α (eukaryotic initiation factor 2α)-ATF4 (activating transcription factor 4)-CHOP (CCAAT-enhancer-binding protein homologous protein) apoptotic signal transduction pathway occurred. Experimental data from use of a siRNA (small interfering RNA) technique, caspase inhibitor, and caspase-3-deficient cell line revealed that TRAIL-induced caspase activation is a prerequisite for the TRAIL-induced ER stress response. TRAIL-induced ER stress was triggered by caspase-8-mediated cleavage of BAP31 (B cell receptor-associated protein 31). The involvement of the proapoptotic PERK-CHOP pathway in TRAIL-induced apoptosis was verified by using a PERK knockout (PERK(-/-) ) mouse embryo fibroblast (MEF) cell line and a CHOP(-/-) MEF cell line. These results suggest that TRAIL-induced the activation of ER stress response plays a role in TRAIL-induced apoptotic death. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 07/2015; DOI:10.1002/jcb.25289 · 3.37 Impact Factor
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    ABSTRACT: Proponents of the robotic platform site its potential advantages in complex reconstructions such as the pancreaticojejunal anastomosis; however, the incidence and risk factors for postoperative pancreatic fistula (POPF) after robotic pancreaticoduodenectomy (RPD) have not been characterized. To identify independent risk factors for POPF after RPD. A prospectively maintained database of patients that underwent RPD (2008-2013) with a standardized pancreaticojejunostomy was analyzed. Univariate and multivariate analyses (UVA/MVA) were used to identify independent predictors for POPF. The POPF prognostic scores developed by Braga and Callery for open pancreaticoduodenectomy were then applied with logistic regression analysis on this RPD cohort. One hundred and fifty consecutive RPDs were analyzed. POPF occurred in 26 (17.3 %); 13 (8.6 %) of which were ISGPF category B and C. On UVA, patients with POPF had larger body mass index (BMI), smaller pancreatic duct diameter, smaller tumor size, longer OR time, larger estimated blood loss (EBL) and RBC transfusion (all p < 0.05). Higher EBL, duct size <4 mm, larger BMI and small tumor size remained the best independent risk factors for POPF on MVA. Increased Callery (OR 1.46, 95 % CI, p = 0.001) and Braga (OR 1.2, 95 % CI, p = 0.005) scores predicted an increased risk of POPF in this RPD cohort. Larger BMI, higher EBL, smaller tumor size and smaller duct diameter are the main predictors of POPF in RPD.
    Surgical Endoscopy 07/2015; DOI:10.1007/s00464-015-4366-8 · 3.31 Impact Factor
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    ABSTRACT: In adrenal tumors, size ≥4 cm has been an indication for adrenalectomy due to concern for malignancy. We compared mass size to imaging features (ImF) for accuracy in diagnosing adrenal malignancy. Data were retrieved for 112 consecutive patients who had adrenalectomy from January 2011 to August 2014. ImF was classified as nonbenign if HU > 10 on unenhanced CT scan or if loss of signal on out-of-phase imaging was absent on chemical-shift MRI. Indications for resection included hormonal hypersecretion, nonbenign ImF, and/or size ≥4 cm. Of 113 resected adrenals, 37 % were functional. Histologic malignancy occurred in 18 % (20/113) and included 3 adrenocortical carcinomas (ACC), 1 epithelioid liposarcoma, 1 lymphoma, 1 malignant nerve sheath tumor, and 14 adrenal metastases. Patients with malignancies were older (mean age, 60 ± 13 vs. 51 ± 14 years, p = 0.01). Malignant tumors were larger on preoperative imaging (mean 5.3 ± 3.2 vs. 3.9 ± 2.4 cm, p = 0.03). All 20 malignant masses had nonbenign ImF. In predicting malignancy, the sensitivity, specificity, NPV, and PPV of nonbenign ImF was 100, 57, 100, and 33 %, respectively. Size ≥4 cm was less predictive with sensitivity, specificity, NPV, and PPV of 55, 61, 86, and 23 %, respectively. If size ≥4 cm had been used as the sole criterion for surgery, 45 % of malignancies (9/20) would have been missed including 8 metastases and an ACC. In resected adrenal tumors, the presence of nonbenign ImF is more sensitive for malignancy than mass size (100 vs. 55 %) with equivalent specificity. Regardless of mass size, adrenalectomy should be strongly considered when non-benign ImF are present.
    Annals of Surgical Oncology 06/2015; DOI:10.1245/s10434-015-4684-z · 3.94 Impact Factor
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    ABSTRACT: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) are used to treat peritoneal carcinomatosis from a variety of primary tumor sites. Little is known about the in vivo effects of CRS and HIPEC. We examined tumor and non-neoplastic peritoneal tissue samples from 38 patients undergoing CRS and HIPEC for appendiceal or colorectal carcinomatosis, using conventional histologic analysis and immunohistochemical analysis for markers of early DNA damage (phosphorylated H2AX, γH2AX) and early necrosis (extracellular HMGB1). Findings were correlated with clinicopathologic features and oncologic outcome. Histologic findings corresponding with CRS and HIPEC included extensive submesothelial inflammatory infiltrate, endothelial activation, mesothelial karyolysis and surface fibrin deposition. Endothelial activation in submesothelial vessels exhibited high specificity for samples obtained following HIPEC relative to samples obtained following CRS but prior to HIPEC. Mesothelial nuclear γH2AX staining and submesothelial extracellular HMGB1 staining increased progressively following CRS and HIPEC, consistent with DNA damage and necrosis. No significant increase in tumor staining for markers was seen with CRS or HIPEC. Submesothelial HMGB1 staining was associated with increased progression-free survival on univariate analysis. The immediate histologic effects of CRS and HIPEC are defined and provide evidence that DNA damage and early steps of necrosis are underway in mesothelial tissues at the conclusion of the procedure. Further research will be necessary to investigate the impact of these findings on long-term oncologic outcome, and may provide insight into the downstream effects of CRS and HIPEC that could facilitate refinement of regional therapeutic regimens for carcinomatosis.
    Annals of Surgical Oncology 05/2015; DOI:10.1245/s10434-015-4580-6 · 3.94 Impact Factor
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    ABSTRACT: Autophagy is a cell survival mechanism that plays a critical role in pancreatic carcinogenesis. Murine studies have previously demonstrated that treatment with the late-autophagy inhibitor chloroquine in combination with chemotherapy limited tumor growth. In this phase 1/2 trial, we examined treatment with hydroxychloroquine (HCQ) and gemcitabine for patients with pancreatic adenocarcinoma. The primary endpoints were safety and tolerability, evaluated by Storer's dose escalation design. Secondary endpoints were CA 19-9 biomarker response, R0 resection rates, survival, and correlative studies of autophagy. Thirty-five patients were enrolled. There were no dose-limiting toxicities and no grade 4/5 events related to treatment. Nineteen patients (61 %) had a decrease in CA 19-9 after treatment. Twenty-nine patients (94 %) underwent surgical resection as scheduled, with a 77 % R0 resection rate. Median overall survival was 34.8 months (95 % confidence interval, 11.57 to not reached). Patients who had more than a 51 % increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free survival (15.03 vs. 6.9 months, p < 0.05) and overall survival (34.83 vs. 10.83 months, p < 0.05). No outcome differences were demonstrated in the 81 % of patients with abnormal p53 expression assessed by immunohistochemistry in the resected specimens. Preoperative autophagy inhibition with HCQ plus gemcitabine is safe and well tolerated. Surrogate biomarker responses (CA 19-9) and surgical oncologic outcomes were encouraging. p53 status was not associated with adverse outcomes.
    Annals of Surgical Oncology 04/2015; DOI:10.1245/s10434-015-4566-4 · 3.94 Impact Factor
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    ABSTRACT: Robotic distal pancreatectomy (RDP) is performed increasingly, but knowledge of the number of cases required to attain procedural proficiency is lacking. The aim of this study was to identify the learning curve associated with RDP at a high-volume pancreatic centre. Metrics of perioperative safety and efficiency for all consecutive RDPs were evaluated. Outcomes were followed to 90 days. Cumulative sum (CUSUM) analysis was used to identify inflexion points corresponding to the learning curve. Between 2008 and 2013, 100 patients underwent RDP. There was no 90-day mortality. In two patients (2.0%), surgery was converted to laparotomy. Thirty procedures were performed for pancreatic adenocarcinoma. Precipitous operative time reductions from an initial operative time of 331 min were observed after the first 20 and 40 cases to 266 min and 210 min, respectively (P < 0.0001). The likelihood of readmission was significantly lower after the first 40 cases (P = 0.04), and non-significant reductions were observed in incidences of major (Clavien-Dindo Grade II or higher) morbidity and Grade B and C leaks, and length of stay. In this experience, RDP outcomes were optimized after 40 cases. Familiarity with the platform and dedicated training are likely to contribute to significantly shorter learning curves in future adopters. © 2015 International Hepato-Pancreato-Biliary Association.
    HPB 04/2015; 17(7). DOI:10.1111/hpb.12412 · 2.05 Impact Factor
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    ABSTRACT: Background Hepatic arterial anomalies (HAAs) are not infrequently encountered during pancreatic resections. In view of the current emergence of the robotic platform as a safe alternative to open surgery in experienced centres, this study sought to determine the implications of HAAs on the safety and oncologic outcomes of robotic pancreaticoduodenectomy (RPD).MethodsA prospectively maintained database of patients with HAAs who underwent RPD (RPD + HAA) at a single institution between 2008 and 2013 was retrospectively reviewed. Demographic information and perioperative outcomes of RPD were compared for patients with and without HAAs.ResultsA total of 142 patients underwent RPD; 112 (78.9%) did not have and 30 (21.1%) did have HAAs. The majority (90.0%) of RPDs in patients with HAAs were performed for malignant indications and all aberrant vessels were preserved without conversion to laparotomy. There were no statistically significant differences between RPD patients with and without HAAs with respect to preoperative demographics, tumour characteristics, operative metrics (operative time, estimated blood loss, conversion) and postoperative outcomes, including complications, length of stay and readmissions. Negative margin (R0) rates were similar in both groups.Conclusions Robot-assisted pancreaticoduodenectomy is safe and feasible in patients with HAAs and has outcomes similar to those in patients with normal arterial anatomy.
    HPB 04/2015; 17(7). DOI:10.1111/hpb.12414 · 2.05 Impact Factor
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    ABSTRACT: Excessive accumulation of mucin 2 (MUC2) protein (a gel-forming secreted mucin) within the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP), a unique mucinous malignancy of the appendix. Mitogen-activated protein kinase (MAPK) signaling pathway is upregulated in PMP and has been shown to modulate MUC2 promoter activity. We hypothesized that targeted inhibition of the MAPK pathway would be a novel, effective, and safe therapeutic strategy to reduce MUC2 production and mucinous tumor growth. We tested RDEA119, a specific MEK1/2 (MAPK/extracellular signal-regulated kinase [ERK] kinase) inhibitor, in MUC2-secreting LS174T cells, human PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. RDEA119 reduced ERK1/2 phosphorylation and inhibited MUC2 messenger RNA and protein expression in vitro. In the xenograft model, chronic oral therapy with RDEA119 inhibited mucinous tumor growth in an MAPK pathway-dependent manner and this translated into a significant improvement in survival. RDEA119 downregulated phosphorylated ERK1/2 and nuclear factor κB p65 protein signaling and reduced AP1 transcription factor binding to the MUC2 promoter in LS174T cells. This study provides a preclinical rationale for the use of MEK inhibitors to treat patients with PMP. Copyright © 2015 Elsevier Inc. All rights reserved.
    03/2015; DOI:10.1016/j.trsl.2015.03.004
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    ABSTRACT: The Ninth International Symposium on Regional Therapies at Steamboat Springs, Colorado brought forth some of the finest research occurring in the management of advanced malignancies. We are pleased to present some of this work in the Annals of Surgical Oncology. Although it is difficult to do justice to the perseverance of the teams, the investigation of the scientists, and the sacrifices of our patients in a few pages, we hope to provide you with a snapshot of a rapidly changing field. Delivering cytotoxic therapy in a proinflammatory healing state after an operation requires the development of a precise framework—the hallmark of regional therapies. Advancement of care has required rapid intuitive thinking and development of surgical concepts that have allowed us to apply selective regional therapies to patients more widely than ever before. It is estimated that more than 1,300 cytoreductive procedures and hyperthermic intraperitoneal chemotherapy (HIPEC) procedures were performed in ...
    Annals of Surgical Oncology 03/2015; 22(5). DOI:10.1245/s10434-015-4426-2 · 3.94 Impact Factor
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    ABSTRACT: Quality assessment is an important instrument to ensure optimal surgical outcomes, particularly during the adoption of new surgical technology. The use of the robotic platform for complex pancreatic resections, such as the pancreaticoduodenectomy, requires close monitoring of outcomes during its implementation phase to ensure patient safety is maintained and the learning curve identified. To report the results of a quality analysis and learning curve during the implementation of robotic pancreaticoduodenectomy (RPD). A retrospective review of a prospectively maintained database of 200 consecutive patients who underwent RPD in a large academic center from October 3, 2008, through March 1, 2014, was evaluated for important metrics of quality. Patients were analyzed in groups of 20 to minimize demographic differences and optimize the ability to detect statistically meaningful changes in performance. Robotic pancreaticoduodenectomy. Optimization of perioperative outcome parameters. No statistical differences in mortality rates or major morbidity were noted during the study. Statistical improvements in estimated blood loss and conversions to open surgery occurred after 20 cases (600 mL vs 250 mL [P = .002] and 35.0% vs 3.3% [P < .001], respectively), incidence of pancreatic fistula after 40 cases (27.5% vs 14.4%; P = .04), and operative time after 80 cases (581 minutes vs 417 minutes [P < .001]). Complication rates, lengths of stay, and readmission rates showed continuous improvement that did not reach statistical significance. Outcomes for the last 120 cases (representing optimized metrics beyond the learning curve) included a mean operative time of 417 minutes, median estimated blood loss of 250 mL, a conversion rate of 3.3%, 90-day mortality of 3.3%, a clinically significant (grade B/C) pancreatic fistula rate of 6.9%, and a median length of stay of 9 days. Continuous assessment of quality metrics allows for safe implementation of RPD. We identified several inflexion points corresponding to optimization of performance metrics for RPD that can be used as benchmarks for surgeons who are adopting this technology.
    03/2015; 150(5). DOI:10.1001/jamasurg.2015.17
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    ABSTRACT: TRAIL has been shown to induce apoptosis in cancer cells, but in some cases, certain cancer cells are resistant to this ligand. In this study, we explored the ability of representative HSP90 (heat shock protein 90) inhibitor NVP-AUY922 to overcome TRAIL resistance by increasing apoptosis in colorectal cancer (CRC) cells. The combination of TRAIL and NVP-AUY922 induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The treatment of NVP-AUY922 dephosphorylated JAK2 and STAT3 and decreased Mcl-1, which resulted in facilitating cytochrome c release. NVP-AUY922-mediated inhibition of JAK2/STAT3 signaling and down-regulation of their target gene, Mcl-1, occurred in a dose and time-dependent manner. Knock down of Mcl-1, STAT3 inhibitor or JAK2 inhibitor synergistically enhanced TRAIL-induced apoptosis. Taken together, our results suggest the involvement of the JAK2-STAT3-Mcl-1 signal transduction pathway in response to NVP-AUY922 treatment, which may play a key role in NVP-AUY922-mediated sensitization to TRAIL. By contrast, the effect of the combination treatments in non-transformed colon cells was minimal. We provide a clinical rationale that combining HSP90 inhibitor with TRAIL enhances therapeutic efficacy without increasing normal tissue toxicity in CRC patients. Copyright © 2014. Published by Elsevier Inc.
    Cellular Signalling 11/2014; 27(2). DOI:10.1016/j.cellsig.2014.11.013 · 4.47 Impact Factor
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    ABSTRACT: Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) is routinely used to treat certain peritoneal carcinomatoses (PC), but it can be associated with relatively high complication rates, prolonged hospital length of stay, and potential mortality. Our objective was to determine the learning curve (LC) of CRS/HIPEC in our high-volume institution. Methods A total of 370 patients with PC from mucinous appendiceal neoplasms (MAN = 282), malignant peritoneal mesothelioma (MPM = 60), and gastric cancer (GC = 24) were studied. Outcomes analyzed included incomplete cytoreduction (IC), severe morbidity (SM), 60-day mortality, progression-free survival (PFS), and overall survival (OS). Risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of CRS/HIPEC for IC and SM using prespecified odds ratio (OR) boundaries derived from previously published data. Risk adjusted-cumulative average probability (RA-CAP) was used to analyze 1-year PFS and 2-year OS. Results Complete cytoreduction, severe morbidity, and 60-day mortality were 84.2, 30, and 1.9 % respectively. Higher simplified peritoneal cancer index was the major independent risk factor for IC, whereas high-grade histology, IC, and diagnosis of MPM and GC (compared with MAN) were predictors of SM after CRS/HIPEC (p SPRT showed that approximately 180 cases are needed to achieve the lowest risk of IC and SM. Ninety cases were needed to achieve a steady 1-year PFS and 2-year OS in RA-CAP plots. Conclusions The completeness of cytoreduction, morbidity, and mortality rates for CRS/HIPEC at our institution are comparable to previously reported data. Approximately 180 and 90 procedures are required to improve operative and oncologic outcomes respectively.
    Annals of Surgical Oncology 11/2014; 22(5). DOI:10.1245/s10434-014-4111-x · 3.94 Impact Factor
  • 11/2014; 2(Suppl 3):P239-P239. DOI:10.1186/2051-1426-2-S3-P239
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    ABSTRACT: Unresectable colorectal liver metastases remain a major unresolved issue and more effective novel regimens are urgently needed. While screening synergistic drug combinations for colon cancer therapy, we identified a novel multidrug treatment for colon cancer: chemotherapeutic agent melphalan in combination with proteasome inhibitor bortezomib and mTOR (mammalian target of rapamycin) inhibitor rapamycin. We investigated the mechanisms of synergistic antitumor efficacy during the multidrug treatment. All experiments were performed with highly metastatic human colon cancer CX-1 and HCT116 cells, and selected critical experiments were repeated with human colon cancer stem Tu-22 cells and mouse embryo fibroblast (MEF) cells. We used immunochemical techniques to investigate a cross-talk between apoptosis and autophagy during the multidrug treatment. We observed that melphalan triggered apoptosis, bortezomib induced apoptosis and autophagy, rapamycin caused autophagy and the combinatorial treatment-induced synergistic apoptosis, which was mediated through an increase in caspase activation. We also observed that mitochondrial dysfunction induced by the combination was linked with altered cellular metabolism, which induced adenosine monophosphate-activated protein kinase (AMPK) activation, resulting in Beclin-1 phosphorylated at Ser 93/96. Interestingly, Beclin-1 phosphorylated at Ser 93/96 is sufficient to induce Beclin-1 cleavage by caspase-8, which switches off autophagy to achieve the synergistic induction of apoptosis. Similar results were observed with the essential autophagy gene, autophagy-related protein 7, -deficient MEF cells. The multidrug treatment-induced Beclin-1 cleavage was abolished in Beclin-1 double-mutant (D133A/D146A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. These observations identify a novel mechanism for AMPK-induced apoptosis through interplay between autophagy and apoptosis.
    Cell Death & Disease 10/2014; 5:e1504. DOI:10.1038/cddis.2014.463 · 5.18 Impact Factor
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    ABSTRACT: Background Postoperative pancreatic fistulas (POPFs) are potentially morbid complications that often require therapeutic interventions. Distal pancreatectomy performed during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) puts patients at risk for POPF. The authors hypothesized that POPFs are more severe after CRS/HIPEC than after pancreatectomy alone. Methods Clinicopathologic and perioperative details, including POPF by International Study Group of Pancreatic Fistula criteria (ISGPF), and oncologic outcomes for patients undergoing distal pancreatectomy during CRS/HIPEC for peritoneal carcinomatosis of appendiceal (n = 31) or colorectal (n = 23) origin (HIPEC group) were compared with those for patients undergoing minimally invasive or open distal pancreatectomy without HIPEC (n = 66) for locally resectable pancreatic adenocarcinoma (non-HIPEC group). Results The incidence of POPF was similar between the HIPEC and non-HIPEC groups (26 %). The severity of POPF according to the ISGPF criteria was significantly worse in the HIPEC group. The HIPEC patients had 13 grade B fistulas and 1 grade C fistula compared with 12 grade A fistulas and 4 grade B fistulas in the non-HIPEC group. The HIPEC patients with POPF did not differ in the extent of their CRS, peritoneal cancer index, length of hospital stay, or other postoperative complications from the the HIPEC patients without POPF. The HIPEC patients with colorectal carcinomatosis who experienced POPF had higher disease recurrence in the first year after CRS/HIPEC than those without POPF. Conclusion The findings showed that POPFs are more severe when distal pancreatectomy is combined with CRS/HIPEC. Moreover, selective use of distal pancreatectomy is important during CRS/HIPEC because POPFs may increase early disease recurrence for patients with colorectal carcinomatosis.
    Annals of Surgical Oncology 10/2014; 22(5). DOI:10.1245/s10434-014-4186-4 · 3.94 Impact Factor
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    ABSTRACT: Benign duodenal and periampullary tumors are uncommon lesions requiring careful attention to their complex anatomic relationships with the major and minor papillae as well as the gastric outlet during surgical intervention. While endoscopy is less morbid than open resection, many lesions are not amenable to endoscopic removal. Robotic surgery offers technical advantages above traditional laparoscopy, and we demonstrate the safety and feasibility of this approach for a variety of duodenal lesions.
    Journal of Gastrointestinal Surgery 10/2014; 19(2). DOI:10.1007/s11605-014-2668-0 · 2.39 Impact Factor
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    ABSTRACT: A hypoxic tumor microenvironment is characteristic of many cancer types, including one of the most lethal, pancreatic cancer. We recently demonstrated that the receptor for advanced glycation end products (RAGE) has an important role in promoting the development of pancreatic cancer and attenuating the response to chemotherapy. We now demonstrate that binding of RAGE to oncogenic KRAS facilitates hypoxia-inducible factor 1 (HIF1)α activation and promotes pancreatic tumor growth under hypoxic conditions. Hypoxia induces NF-κB-dependent and HIF1α-independent RAGE expression in pancreatic tumor cells. Moreover, the interaction between RAGE and mutant KRAS increases under hypoxia, which in turn sustains KRAS signaling pathways (RAF-MEK-ERK and PI3K-AKT), facilitating stabilization and transcriptional activity of HIF1α. Knock down of RAGE in vitro inhibits KRAS signaling, promotes HIF1α degradation, and increases hypoxia-induced pancreatic tumor cell death. RAGE-deficient mice have impaired oncogenic KRAS-driven pancreatic tumor growth with significant downregulation of the HIF1α signaling pathway. Our results provide a novel mechanistic link between NF-κB, KRAS, and HIF1α, three potent molecular pathways in the cellular response to hypoxia during pancreatic tumor development and suggest alternatives for preventive and therapeutic strategies.
    Cell Death & Disease 10/2014; 5(10):e1480. DOI:10.1038/cddis.2014.445 · 5.18 Impact Factor
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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; 29(6). DOI:10.1007/s00464-014-3803-4 · 3.31 Impact Factor
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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 08/2014; 19(11). DOI:10.1007/s10495-014-1028-6 · 3.61 Impact Factor
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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. All patients receiving neoadjuvant therapy for PDA from July 2010 to February 2013 were retrospectively reviewed. Resection rate, R0 resection rate, need for venous resection, and overall survival were correlated to CA 19-9 response. Fisher's exact test, Kaplan-Meier survival analysis, and multivariate analysis using Cox regression were used. A total of 78 patients were studied (21 patients with resectable disease, 40 borderline resectable, and 17 with locally advanced disease). A variety of chemotherapies +/- A radiation were utilized during the study period. Overall, 56 patients (72 %) had a decrease in CA 19-9 of > 50 % with neoadjuvant treatment. In borderline resectable patients, CA 19-9 response of > 50 % predicted R0 resection (odds ratio 4.2; p = 0.05). In borderline resectable patients who had an increase in CA 19-9, none of five (0 %) underwent R0 resection compared with 80 % of the remaining cohort (p = 0.001). The complete pathologic response rate was 29 % in patients who had a CA 19-9 response of > 90 % versus 0 % in the remaining patients (p < 0.001). A CA 19-9 response of > 50 % resulted in improved overall survival (28.0 vs. 11.1 months; p < 0.0001) and was an independent predictor of survival (hazard ratio 0.26; 95 % CI 0.13-0.55; p < 0.0001). CA 19-9 response to neoadjuvant therapy is associated with R0 resection rate, histopathologic response, and survival. Incorporation of this easily obtainable biomarker into future clinical trials may facilitate more rapid evaluation of novel regimens.
    Annals of Surgical Oncology 08/2014; 21(13). DOI:10.1245/s10434-014-3842-z · 3.94 Impact Factor

Publication Stats

6k Citations
1,154.97 Total Impact Points

Institutions

  • 2001–2015
    • University of Pittsburgh
      • • Division of Surgical Oncology
      • • Department of Surgery
      Pittsburgh, Pennsylvania, United States
    • NCI-Frederick
      Фредерик, Maryland, United States
    • Cancer Research and Biostatistics
      Seattle, Washington, United States
  • 2012
    • Gulhane Military Medical Academy
      Engüri, Ankara, Turkey
    • University of Florida
      Gainesville, Florida, United States
    • Krankenhaus Barmherzige Brüder Regensburg
      Ratisbon, Bavaria, Germany
  • 1998–2011
    • National Cancer Institute (USA)
      • • Surgery Branch
      • • Center for Cancer Research
      Maryland, United States
  • 1997–2009
    • National Institutes of Health
      • • Branch of Surgery
      • • Section on Human Iron Metabolism
      Maryland, United States
  • 2004
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 2001–2002
    • National Institute of Allergy and Infectious Diseases
      베서스다, Maryland, United States
  • 1999
    • University of Vienna
      Wien, Vienna, Austria
    • Technische Universität München
      München, Bavaria, Germany
  • 1996
    • University of Pennsylvania
      • Department of Surgery
      Philadelphia, Pennsylvania, United States