Sunil Singhal

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (72)291.75 Total impact

  • International journal of radiation oncology, biology, physics 11/2014; 90(5). · 4.59 Impact Factor
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    ABSTRACT: Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%-25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62LloCD54hi) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses.
    Journal of Clinical Investigation 11/2014; · 12.81 Impact Factor
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    ABSTRACT: Surgical biopsy of potential tumor recurrence is a common challenge facing oncologists, surgeons, and cancer patients. Imaging modalities have limited ability to accurately detect recurrent cancer in fields affected by previous surgery, chemotherapy, or radiation. However, definitive tissue diagnosis is often needed to initiate treatment and to direct therapy. We sought to determine if a targeted fluorescent intraoperative molecular imaging technique could be applied in a clinical setting to assist a surgical biopsy in a "hostile" field. We describe the use of a folate-fluorescein conjugate to direct the biopsy of a suspected recurrent lung adenocarcinoma invading the mediastinum that had been previously treated with chemoradiation. We found that intraoperative imaging allowed the identification of small viable tumor deposits that were otherwise indistinguishable from scar and necrosis. Our operative observations were confirmed by histology, fluorescence microscopy, and immunohistochemistry. Our results demonstrate one possible application and clinical value of intraoperative molecular imaging.
    Molecular imaging. 11/2014; 13:1-6.
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    ABSTRACT: Careful preparation of human tissues is the cornerstone of obtaining accurate data in immunologic studies. Despite the essential importance of tissue processing in tumor immunology and clinical medicine, current methods of tissue disaggregation have not been rigorously tested for data fidelity. Thus, we critically evaluated the current techniques available in the literature that are used to prepare human lung tumors for immunologic studies. We discovered that these approaches are successful at digesting cellular attachments and ECMs; however, these methods frequently alter the immune cell composition and/or expression of surface molecules. We thus developed a novel approach to prepare human lung tumors for immunologic studies by combining gentle mechanical manipulation with an optimized cocktail of enzymes used at low doses. This enzymatic digestion cocktail optimized cell yield and cell viability, retrieved all major tumor-associated cell populations, and maintained the expression of cell-surface markers for lineage definition and in vivo effector functions. To our knowledge, we present the first rigorously tested disaggregation method designed for human lung tumors.
    Journal of leukocyte biology. 10/2014;
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    ABSTRACT: Background: Gene therapy is currently under investigation as a means of managing a variety of pulmonary diseases. Unfortunately, gene transfer to bronchial epithelium has been hampered by the lack of stable and efficient transduction. Recent studies have shown that gene vectors could be tethered to the metallic surfaces of intra-arterial stents. This approach enables efficacious and site-specific adenoviral gene delivery to the vascular endothelium. Objectives: We hypothesized that airway mesh stents impregnated with viral gene vectors could be used for local gene delivery to benign and malignant bronchial epithelium. Methods: Serotype 5 adenoviral vectors (Ad5, E1-/E3-) containing the reporter genes green fluorescent protein (Ad.GFP) or β-galactoside/LacZ (Ad.LacZ), or a therapeutic gene, Ad.INF-β, were coupled to either metallic mesh disks or stents via anti-Ad knob antibodies. These platforms were assessed for their ability to transfect bronchial epithelial cells from both rats and humans, as well as murine (L1C2) and human (A549) lung cancer cell lines. Gene transfer was quantified by fluorescent microscopy, scanning fluorimetry for Ad.GFP, and light microscopy studies assessing β-galactosidase staining for Ad.LacZ. Metallic mesh and stent-mediated gene transfer was also performed in a murine flank tumor model and in a rat endotracheal tumor model in order to evaluate the therapeutic potential. Results: In these studies, murine and human non-small cell lung cancer (NSCLC) cells were successfully transfected with reporter genes in vitro. Ad.LacZ-complexed mesh successfully transfected reporter genes into established murine flank NSCLC tumors. In addition, Ad.LacZ-tethered stents could effectively transfect both tracheobronchial epithelium and submucosal glands in rats. Similar epithelial transfection was achieved in ex vivo human bronchial epithelium. Pilot in vivo experimentation provided data supporting the concept that therapeutic genes could also be delivered with this technology. In additional pilot in vivo experiments, the growth of murine flank tumors was inhibited by placement of mesh disks coupled with Ad.muINF-β, and rats bearing endotracheal tumors demonstrated a trend towards prolonged survival with insertion of Ad.ratINF-β-tethered stents. Conclusions: Stent-mediated gene delivery successfully enabled site-specific vector administration to target rat and human airway cells in cell culture, organ culture and in vivo. Local tracheobronchial gene delivery via stents could provide a viable clinical solution for overcoming the difficulties encountered with vector delivery within the lungs, in particular by lowering requisite vector titers and by directing desired vectors to areas of interest. This strategy may prove valuable for treating tumors involving the tracheobronchial tree, as well as other nonmalignant tracheobronchial disorders. © 2014 S. Karger AG, Basel.
    10/2014;
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    ABSTRACT: Defining tumor from non-tumor tissue is one of the major challenges of cancer surgery. Surgeons depend on visual and tactile clues to select which tissues should be removed from a patient. Recently, we and others have hypothesized near-infrared (NIR) imaging can be used during surgery to differentiate tumors from normal tissue.
    PLoS ONE 07/2014; 9(7):e103342. · 3.53 Impact Factor
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    ABSTRACT: Several studies have indicated that diaphragm dysfunction develops in patients on mechanical ventilation (MV). Here, we tested the hypothesis that the contractility of sarcomeres - i.e. the smallest contractile unit in muscle - is affected in humans on MV. To this end, we compared diaphragm muscle fibers of 9 brain-dead organ donors (cases) who had been on MV for 26 ± 5 hours with diaphragm muscle fibers from 9 patients (controls) undergoing surgery for lung cancer who had been on MV less than 2 hours. In each diaphragm specimen we determined (1) muscle fiber cross-sectional area in cryosections by immunohistochemical methods, and (2) the contractile performance of permeabilized single muscle fibers by means of maximum specific force, kinetics of cross-bridge cycling by rate of tension redevelopment, myosin heavy chain content and concentration, and calcium sensitivity of force of slow-twitch and fast-twitch muscle fibers. In case subjects we noted no statistically significant decrease in outcomes compared to controls in slow-twitch or fast-twitch muscle fibers. These observations indicate that 26 hours of MV of humans is not invariably associated with changes in the contractile performance of sarcomeres in the diaphragm.
    American journal of physiology. Lung cellular and molecular physiology. 07/2014;
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    ABSTRACT: Despite recent advances in the development of novel therapies, esophageal carcinoma remains an aggressive cancer associated with a poor prognosis. The lack of a high throughput, reproducible syngeneic animal model that replicates human disease is partly responsible for the paucity of novel therapeutic approaches. In this report, we present the first successful syngeneic, orthotopic model for esophageal cancer. This model was used to test an established adenoviral-based tumor vaccine. We utilized a murine esophageal cancer cell line established from the ED-L2-cyclin D1;p53 mouse that was transduced to express a viral tumor antigen, the Human Papilloma Virus (HPV) E7 protein. The tumor was established in its natural microenvironment at the gastroesophageal junction. Tumor growth was consistent and reproducible. An adenoviral vaccine to E7 (Ad.E7) induced an E7-specific population of functionally active CD8 T cells that trafficked into the tumors and retained cytotoxicity. Ad.E7 vaccination reduced local tumor growth and prolonged overall survival. These findings suggest that orthotopic tumor growth is a reasonable preclinical model to validate novel therapies.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 06/2014; 37(5):283-92. · 3.20 Impact Factor
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    ABSTRACT: Induced Forkhead box P3-positive (Foxp3(+)) T-regulatory cells (iTregs) are essential to gastrointestinal immune homeostasis, and loss of the ability to develop iTregs may lead to autoimmune colitis. We previously showed a role for sirtuin-1 (Sirt1) in control of Treg function and hypothesized that targeting of Sirt1 might enhance iTreg development and thereby represent a potential therapy for inflammatory bowel disease (IBD). We adoptively transferred CD4(+)CD25(-)Foxp3(-) T effector (TE) cells from wild-type (WT) (C57BL/6) or fl-Sirt1/CD4cre mice into B6/Rag1(-/-) mice and monitored the mice until they lost 10-15% of their weight. Adoptive transfer of TE cells lacking Sirt1 to B6/Rag1(-/-) mice resulted in a 2.8-fold increase in iTreg formation compared with mice receiving WT TE cells and correlated with attenuated colitis and reduced weight loss (1.04±1.4% vs. 13.97±2.2%, respectively, P<0.001). In a second model of IBD, we used pharmacologic Sirt1 targeting of mice receiving multiple cycles of dextran sodium sulfate (DSS) in their drinking water, alternated with fresh water. Likewise, WT mice receiving cyclic DSS and a Sirt1 inhibitor, EX-527, had reduced weight loss (5.8±5.9% vs. 13.2±6.9%, respectively, P=0.03) and increased iTreg formation compared with controls. Sirt1 appears a promising target for pharmacologic therapy of IBD as a result of promoting iTreg development.Mucosal Immunology advance online publication, 19 February 2014; doi:10.1038/mi.2014.10.
    Mucosal Immunology 02/2014; · 7.54 Impact Factor
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    ABSTRACT: This compares outcome measures of current pectus excavatum (PEx) treatments, namely the Nuss and Ravitch procedures, in pediatric and adult patients. Original investigations that stratified PEx patients based on current treatment and age (pediatric = 0-21; adult 17-99) were considered for inclusion. Outcome measures were: operation duration, analgesia duration, blood loss, length of stay (LOS), outcome ratings, complications, and percentage requiring reoperations. Adult implant patients (18.8%) had higher reoperation rates than adult Nuss or Ravitch patients (5.3% and 3.3% respectively). Adult Nuss patients had longer LOS (7.3 days), more strut/bar displacement (6.1%), and more epidural analgesia (3 days) than adult Ravitch patients (2.9 days, 0%, 0 days). Excluding pectus bar and strut displacements, pediatric and adult Nuss patients tended to have higher complication rates (pediatric - 38%; adult - 21%) compared to pediatric and adult Ravitch patients (12.5%; 8%). Pediatric Ravitch patients clearly had more strut displacements than adult Ravitch patients (0% and 6.4% respectively). These results suggest significantly better results in common PEx surgical repair techniques (i.e. Nuss and Ravitch) than uncommon techniques (i.e. Implants and Robicsek). The results suggest slightly better outcomes in pediatric Nuss procedure patients as compared with all other groups. We recommend that symptomatic pediatric patients with uncomplicated PEx receive the Nuss procedure. We suggest that adult patients receive the Nuss or Ravitch procedure, even though the long-term complication rates of the adult Nuss procedure require more investigation.
    Journal of Cardiothoracic Surgery 02/2014; 9(1):25. · 0.90 Impact Factor
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    ABSTRACT: The mechanisms by which tumor-associated neutrophils (TAN) affect tumor growth are to a large extent unknown. Regulatory T cells (T-regs) are functionally immune-suppressive subsets of T-cells. Depletion or inhibition of T-regs can enhance anti-tumor immunity. We demonstrated both by RT-PCR and ELISA, that murine TAN secrete significant amounts of the T-regs chemoattractant, CCL17, much more than circulating or splenic neutrophils, and at a level progressively increasing during tumor development. Migration assays, both in vitro and in vivo, showed recruitment of T-regs by TAN which was inhibited with anti-CCL17 monoclonal antibodies. Systemic neutrophil depletion in tumor-bearing mice using anti-Ly6G monoclonal antibodies reduced the migration of T-regs into the tumors. We further showed, using flow cytometry, that CCL17 secretion by TAN is not limited to mouse models of cancer but is also relevant to human TAN. Our results suggest a new indirect mechanism by which TAN may inhibit anti-tumor immune activity, thus promoting tumor growth. We further describe, for the first time, a clear link between TAN and regulatory T-cells (T-regs) acting together to impair anti-tumor immunity. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2014; · 6.20 Impact Factor
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    ABSTRACT: Background Over 80,000 people undergo pulmonary resection for a lung nodule in the United States each year. Small nodules are frequently missed or difficult to find despite preoperative imaging. We hypothesized that near-infrared (NIR) imaging technology could be used to identify and locate lung nodules during surgery. Methods We enrolled 18 patients who were diagnosed with a pulmonary nodule that required resection. All patients had a fine-cut 1-mm computed tomography scan preoperatively. The patients were given systemic 5 mg/kg indocyanine green and then underwent an open thoracotomy 24 hours later. The NIR imaging was used to identify the primary nodule and search for additional nodules that were not found by visual inspection or manual palpation of the ipsilateral lung. Results Manual palpation and visual inspection identified all 18 primary pulmonary nodules and no additional lesions. Intraoperative NIR imaging detected 16 out of the 18 primary nodules. The NIR imaging also identified 5 additional subcentimeter nodules; 3 metastatic adenocarcinomas and 2 metastatic sarcomas. This technology could identify nodules as small as 0.2 cm and as deep as 1.3 cm from the pleural surface. This approach discovered 3 nodules that were in different lobes than the primary tumor. Nodule fluorescence was independent of size, metabolic activity, histology, tumor grade and vascularity. Conclusions This is the first-in-human demonstration of identifying pulmonary nodules during thoracic surgery with NIR imaging without a priori knowledge of their location or existence. The NIR imaging can detect pulmonary nodules during lung resections that are poorly visualized on computed tomography and difficult to discriminate on finger palpation.
    The Annals of Thoracic Surgery. 01/2014;
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    ABSTRACT: Fluorescence guided surgery (FGS) is a developing field of surgical and oncologic research. Practically, FGS has shown useful applications in urologic surgery, benign biliary surgery, colorectal cancer liver metastasis resection, and ovarian cancer debulking. Most notably in in cancer surgery, FGS allows for the clear delineation of cancerous tissue from benign tissue. FGS requires the utilization of a fluorescent contrast agent and an intraoperative fluorescence imaging device (IFID). Currently available IFIDs are expensive, unable to work with multiple fluorophores, and can be cumbersome. This study aims to describe the development and utility of a small, cost-efficient, and interchangeable IFID made from commercially available components. Extensive research was done to design and construct a light-weight, portable, and cost-effective IFID. We researched the capabilities, size, and cost of several camera types and eventually decided on a near-infrared (NIR) charged couple device (CCD) camera for its overall profile. The small portable interchangeable imager of fluorescence (SPIIF) is a "scout" IFID system for FGS. The main components of the SPIIF are a NIR CCD camera with an articulating light filter. These components and a LED light source with an attached heat sink are mounted on a small metal platform. The system is connected to a laptop by a USB 2.0 cable. Pixielink (c) software on the laptop runs the system by controlling exposure time, gain, and image capture. After developing the system, we evaluated its utility as an IFID. The system weighs less than two pounds and can cover a large area. Due to its small size, it is easily made sterile by covering it with any sterile plastic sheet. To determine the system's ability to detect fluorescent signal, we used the SPIIF to detect indocyanine green under ex and in-vivo conditions and fluorescein under ex-vivo conditions. We found the SPIIF was able to detect both ICG and fluorescein under different depths of a semi-opaque colloid. Second, we found that a concentration as low as 0.5 g/ml of indocyanine green dissolved in plasma was detectable. Lastly, in a murine and human cancer model, the SPIIF was able to detect indocyanine green signal within tumors and generate a signal-to-background ratio (SBR) of 3.75. This study shows that a low-cost IFID can be made from commercially available parts. Second, this IFID is capable of in and ex-vivo detection of multiple fluorophores without sacrificing its small size or favorable ergonomics.
    Technology in cancer research & treatment 12/2013; · 1.94 Impact Factor
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    ABSTRACT: Forkhead box P3 (Foxp3)(+) T regulatory (Treg) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3(+) Treg cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that experimentally depleting Foxp3(+) Treg cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3(+) Treg cells increased T cell receptor-induced apoptosis in Treg cells, impaired Treg cell suppressive function and peripheral Treg cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3(+) Treg cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-molecule inhibitors can diminish Treg cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.
    Nature medicine 08/2013; · 27.14 Impact Factor
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    ABSTRACT: Transforming growth factor (TGF)-beta is a potent immunosuppressive cytokine necessary for cancer growth. Animal and human studies have shown that pharmacologic inhibition of TGF-beta slows the growth rate of established tumors and occasionally eradicates them altogether. We observed, paradoxically, that inhibiting TGF-beta before exposing animals to tumor cells increases tumor growth kinetics. We hypothesized that TGF-beta is necessary for the anti-tumor effects of cytotoxic CD8+ T lymphocytes (CTLs) during the early stages of tumor initiation. BALB/c mice were pretreated with a blocking soluble TGF-beta receptor (sTGF-betaR, TGF-beta-blockade group, n=20) or IgG2a (Control group, n=20) before tumor inoculation. Tumor size was followed for 6 weeks. In vivo lymphocyte assays and depletion experiments were then performed to investigate the immunological basis of our results. Lastly, animals were pretreated with either sTGF-betaR (n=6) or IgG2a (n=6) prior to immunization with an adenoviral vector encoding the human papillomavirus E7 gene (Ad.E7). One week later, flow cytometry was utilized to measure the number of splenic E7-specific CD8+ T cells. Inhibition of TGF-beta before the injection of tumor cells resulted in significantly larger average tumor volumes on days 11, 17, 22, 26, and 32 post tumor-inoculation (p<0.05). This effect was due to the inhibition of CTLs, as it was not present in mice with severe combined immunodeficiency (SCID) or those depleted of CD8+ T cells. Furthermore, pretreatment with sTGF-beta R inhibited tumor-specific CTL activity in a Winn Assay. Tumors grew to a much larger size when mixed with CD8+ T cells from mice pretreated with sTGF-betaR than when mixed with CD8+ T cells from mice in the control group: 96mm3 vs. 22.5mm3, respectively (p<0.05). In addition, fewer CD8+ T cells were generated in Ad.E7-immunized mice pretreated with sTGF-betaR than in mice from the control group: 0.6% total CD8+ T cells vs. 1.9%, respectively (p<0.05). These studies provide the first in vivo evidence that TGF-beta may be necessary for anti-tumor immune responses in certain cancers. This finding has important implications for our understanding of anti-tumor immune responses, the role of TGF-beta in the immune system, and the future development of TGF-beta inhibiting drugs.
    BMC Immunology 07/2013; 14(1):30. · 2.61 Impact Factor
  • David Fedor, W Rainey Johnson, Sunil Singhal
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    ABSTRACT: PURPOSE: To date, few large-scale original studies have focused specifically on local recurrence following curative lung cancer surgery. This review seeks to consolidate and analyze data from these studies regarding local recurrence incidence, risk factors, salvage treatments, and outcomes to increase awareness in the Oncology community and to spark new research in this area. METHODS: PubMed literature was searched for large-scale cohort studies involving recurrence following lung cancer surgery. Studies with a primary focus on local recurrence and studies that examined overall recurrence but provided relevant numerical data on local recurrence were included. Each chosen study's methods were critically analyzed to reconcile as best as possible large differences in reported results across the studies. RESULTS: Up to 24% of patients recur locally following lung cancer surgery. Risk of local recurrence increases with the stage of the primary cancer, but even stage I patients experience local recurrence up to 19% of the time. Overall survival time following local recurrence varies widely across studies, from 7 to 26 months, and may be related to frequency of follow-up visits. Salvage therapy appears to increase survival time. However, estimates of this increase vary widely, and measurements of benefits of the various salvage options are confounded by lack of control of subjects' condition at the time of salvage therapy administration. CONCLUSIONS: Local recurrence following lung cancer surgery is a significant problem warranting additional research. At present, data on this topic is scarce. We recommend initiation of additional large-scale studies to clearly define the parameters of local recurrence in order to provide useful guidance to clinicians.
    Surgical Oncology 05/2013; · 2.14 Impact Factor
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    ABSTRACT: Background:Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy.Methods:We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT-PCR).Results:In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8(+) T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect.Conclusion:Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials.
    British Journal of Cancer 04/2013; 108(6):1288-97. · 5.08 Impact Factor
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    ABSTRACT: The goal of achieving measurable response with cancer immunotherapy requires counteracting the immunosuppressive characteristics of tumors. One of the mechanisms that tumors utilize to escape immunosurveillance is the activation of myeloid derived suppressor cells (MDSCs). Upon activation by tumor-derived signals, MDSCs inhibit the ability of the host to mount an anti-tumor immune response via their capacity to suppress both the innate and adaptive immune systems. Despite their relatively recent discovery and characterization, anti-MDSC agents have been identified, which may improve immunotherapy efficacy.
    Oncoimmunology. 04/2013; 2(4):e24117.
  • W Rainey Johnson, David Fedor, Sunil Singhal
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    ABSTRACT: Pectus excavatum is the most common congenital abnormality of the chest wall. It may lead to adverse psychosocial development and preoccupation with a negative body image. The Nuss procedure is a minimally invasive approach for improving these patients' body image. The most dangerous complication is cardiac perforation from the insertion of the introducer. Our technique modifies this procedure to include a small subxiphoid incision and a novel sternal lift system that elevates the sternum. This facilitates the insertion of the introducer and placement of the pectus bar(s), and it reduces the risk of intraoperative cardiac perforation.
    The Annals of thoracic surgery 03/2013; 95(3):1109-11. · 3.45 Impact Factor
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    ABSTRACT: Each year, more than 700,000 people undergo cancer surgery in the United States. However, more than 40% of those patients develop recurrences and have a poor outcome. Traditionally, the medical community has assumed that recurrent tumors arise from selected tumor clones that are refractory to therapy. However, we found that tumor cells have few phenotypical differences after surgery. Thus, we propose an alternative explanation for the resistance of recurrent tumors. Surgery promotes inhibitory factors that allow lingering immunosuppressive cells to repopulate small pockets of residual disease quickly. Recurrent tumors and draining lymph nodes are infiltrated with M2 (CD11b(+)F4/80(hi)CD206(hi) and CD11b(+)F4/80(hi)CD124(hi)) macrophages and CD4(+)Foxp3(+) regulatory T cells. This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size, an intact antitumor immune response, and unaltered cancer cells. Therapeutic strategies coupling antitumor agents with inhibition of immunosuppressive cells potentially could impact the outcomes of more than 250,000 people each year.
    Proceedings of the National Academy of Sciences 01/2013; 110(5):E415-24. · 9.81 Impact Factor

Publication Stats

1k Citations
291.75 Total Impact Points

Institutions

  • 2003–2014
    • University of Pennsylvania
      • • Department of Biostatistics and Epidemiology
      • • Department of Surgery
      • • Clinical Studies – Philadelphia
      Philadelphia, Pennsylvania, United States
  • 2002–2014
    • Hospital of the University of Pennsylvania
      • • Department of Surgery
      • • Department of Medicine
      • • Division of Cardiothoracic Surgery
      Philadelphia, Pennsylvania, United States
  • 2012
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
    • Emory University
      Atlanta, Georgia, United States
  • 2010
    • Stanford University
      • Department of Cardiothoracic Surgery
      Stanford, CA, United States
  • 2003–2005
    • Johns Hopkins University
      • • Department of Surgery
      • • Department of Medicine
      Baltimore, Maryland, United States