Sunil Singhal

Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (64)268.64 Total impact

  • [Show abstract] [Hide abstract]
    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; · 7.00 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: 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. · 9.74 Impact Factor
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    ABSTRACT: A profound remodeling of the diaphragm and vastus lateralis (VL) occurs in patients with moderate-to-severe COPD. In this mini-review, we discuss the following costal diaphragm remodeling features noted in patients with moderate-to-severe COPD: (a) increased proportion of slow-twitch fibers; (b) fast to slow isoform shift in sarcoendoplasmic reticulum ATPase (SERCA); (c) increased capacity of oxidative metabolism; (d) oxidative stress; and (e) myofiber atrophy. We then present the sole feature of diaphragm remodeling noted in mild-to-moderate COPD under the heading "myosin heavy chain and contractile remodeling noted in mild-to-moderate COPD." The importance of VL remodeling in COPD patients as a prognostic indicator as well as a major determinant of the ability to carry out activities of daily living is well-accepted. We present the remodeling of the VL noted in COPD patients under the following headings: (a) decrease in proportion of slow-twitch fibers; (b) decreased activity of oxidative pathways (c) oxidative and nitrosative stress; and (e) myofiber atrophy. For each of the remodeling features noted in both VL and costal diaphragm of COPD patients, we present mechanisms that are currently thought to mediate these changes as well as the pathophysiology of each remodeling feature. We hope that our mechanistic presentation stimulates pharmacological as well as rehabilitation medicine research that focuses on the ability of COPD patients to carry out increased activities of daily living.
    Journal of Applied Physiology 12/2012; · 3.48 Impact Factor
  • Brendan F Judy, Sunil Singhal
    Immunotherapy 11/2012; 4(11):1077-80. · 2.39 Impact Factor
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    ABSTRACT: Surgical resection remains the most effective therapy for solid tumors worldwide. The most important prognostic indicator for cure following cancer surgery is a complete resection with no residual disease. However, intraoperative detection of retained cancer cells after surgery is challenging, and residual disease continues to be the most common cause of local failure. We hypothesized that visual enhancement of tumors using near-infrared imaging could potentially identify tumor deposits in the wound after resection. A small animal model of surgery and retained disease was developed. Residual tumor deposits in the wound were targeted using an U.S. Food and Drug Administration-approved imaging agent, indocyanine green, by the enhanced permeability and retention effect. A novel handheld spectrometer was used to optically visualize retained disease after surgery. We found residual disease using near-infrared imaging during surgery that was not visible to the naked eye or micro-CT. Furthermore, examination of tumor nodules was remarkably precise in delineating margins from normal surrounding tissues. This approach was most successful for tumors with increased neovasculature. The results suggest that near-infrared examination of the surgical wound after curative resection can potentially enable the surgeon to locate residual disease. The data in this study is the basis of an ongoing Phase I/II clinical trial in patients who undergo resection for lung and breast cancer. Clin Cancer Res; 18(20); 5741-51. ©2012 AACR.
    Clinical Cancer Research 08/2012; 18(20):5741-51. · 7.84 Impact Factor
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    ABSTRACT: Up to 30% of cancer patients undergoing curative surgery develop local recurrences due to positive margins. Patients typically receive adjuvant chemotherapy, immunotherapy and/or radiation to prevent such relapses. Interestingly, evidence supporting these therapies is traditionally derived in animal models of primary tumors, thus failing to consider surgically induced tumor microenvironment changes that may influence adjuvant therapy efficacy. To address this consideration, we characterized a murine model of local cancer recurrence. This model was reproducible and generated a postoperative inflammatory tumor microenvironment that resembles those observed following human cancer surgery. To further validate this model, antagonists of two pro-inflammatory mediators, TGFβ and COX-2, were tested and found to be effective in decreasing the growth of recurrent tumors. We appreciated that preoperative TGFβ inhibition led to wound dehiscence, while postoperative initiation of COX-2 inhibition resulted in a loss of efficacy. In summary, although not an exact replica of all human cancer surgeries, our proposed local recurrence approach provides a biologically relevant and reliable model useful for preclinical evaluation of novel adjuvant therapies. The use of this model yields results that may be overlooked using traditional preclinical cancer models that fail to incorporate a surgical component.
    Cancer biology & therapy 07/2012; 13(9):745-55. · 3.29 Impact Factor
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    ABSTRACT: Multiple immunotherapy approaches have improved adaptive anti-tumor immune responses in patients with early stage disease; however, results have been less dramatic when treating patients with late stage disease. These blunted responses are likely due to a host of factors, including changes in the tumor microenvironment and systemic immunosuppressive features, which accompany advanced tumor states. We hypothesized that cytoreductive surgery could control these immunosuppressive networks and restore the potency of immunotherapy in advanced disease scenarios. To test these hypotheses, two representative intratumoral immunotherapies (an adenoviral vector encoding a suicide gene, AdV-tk, or a type-I interferon, Ad.IFNα) were tested in murine models of lung cancer. Cytoreductive surgery was performed following treatment of advanced tumors. Mechanistic underpinnings were investigated using flow cytometry, in vivo leukocyte depletion methods and in vivo tumor neutralization assays. AdV-tk and Ad.IFNα were effective in treating early lung cancers, but had little anti-tumor effects in late stage cancers. Interestingly, in late stage scenarios, surgical cytoreduction unmasked the anti-tumor potency of both immunotherapeutic approaches. Immune mechanisms that explained restoration in anti-tumor immune responses included increased CD8 T-cell trafficking and reduced myeloid derived suppressor cell populations. This study demonstrates that surgical resection combined with immunotherapy may be a rational therapeutic option for patients with advanced stage cancer.
    Journal of Hematology & Oncology 06/2012; 5:34. · 4.46 Impact Factor
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    ABSTRACT: With the advent of targeted therapies directed towards folate receptor alpha, with several such agents in late stage clinical development, the sensitive and robust detection of folate receptor alpha in tissues is of importance relative to patient selection and perhaps prognosis and prediction of response. The goal of the present study was to evaluate the expression of folate receptor alpha in non-small cell lung cancer specimens to determine its frequency of expression and its potential for prognosis. The distribution of folate receptor alpha expression in normal tissues as well as its expression and relationship to non-small cell lung cancer subtypes was assessed by immunohistochemistry using tissue microarrays and fine needle aspirates and an optimized manual staining method using the recently developed monoclonal antibody 26B3. The association between folate receptor alpha expression and clinical outcome was also evaluated on a tissue microarray created from formalin fixed paraffin embedded specimens from patients with surgically resected lung adenocarcinoma. Folate receptor alpha expression was shown to have a high discriminatory capacity for lung adenocarcinomas versus squamous cell carcinomas. While 74% of adenocarcinomas were positive for folate receptor alpha expression, our results found that only 13% of squamous cell carcinomas were FRA positive (p<0.0001). In patients with adenocarcinoma that underwent surgical resection, increased folate receptor alpha expression was associated with improved overall survival (Hazard Ratio 0.39, 95% CI 0.18-0.85). These data demonstrate the diagnostic relevance of folate receptor alpha expression in non-small cell lung cancer as determined by immunohistochemistry and suggest that determination of folate receptor alpha expression provides prognostic information in patients with lung adenocarcinoma.
    Oncotarget 04/2012; 3(4):414-25. · 6.64 Impact Factor
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    ABSTRACT: Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen. Phosphatidylserine (PS) is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues. Thus, PS is an attractive target for cancer therapy after surgery. Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 (a novel mouse chimeric monoclonal antibody that targets PS), cisplatin (cis), or combination after surgery. Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone (P = .02). Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals. Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells, particularly granulocytes. This strategy was independent of the adaptive immune system. Together, these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery.
    Neoplasia (New York, N.Y.) 04/2012; 14(4):352-9. · 5.48 Impact Factor

Publication Stats

1k Citations
268.64 Total Impact Points

Institutions

  • 2002–2013
    • Hospital of the University of Pennsylvania
      • • Department of Medicine
      • • Division of Cardiothoracic Surgery
      • • Department of Surgery
      Philadelphia, Pennsylvania, United States
  • 2012
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
    • Emory University
      Atlanta, Georgia, United States
  • 2003–2012
    • University of Pennsylvania
      • • Department of Biostatistics and Epidemiology
      • • Department of Surgery
      • • Clinical Studies – Philadelphia
      Philadelphia, Pennsylvania, 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