Richmond, VA, United States
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Le D.T.,Johns Hopkins University | Uram J.N.,Johns Hopkins University | Wang H.,Johns Hopkins University | Bartlett B.R.,Johns Hopkins University | And 32 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P = 0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P = 0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P = 0.02). CONCLUSIONS This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. Copyright © 2015 Massachusetts Medical Society.


Tseng H.-C.,Jane and Jerry Weintraub Center for Reconstructive Biotechnology | Bui V.,Jane and Jerry Weintraub Center for Reconstructive Biotechnology | Man Y.-G.,Bon Secours Cancer Institute | Cacalano N.,University of California at Los Angeles | And 2 more authors.
Frontiers in Immunology | Year: 2014

In this paper, we provide evidence that anergized NK cells through secreted factors and direct cell-cell contact have the ability to induce differentiation of healthy dental pulp stem cells and stem cell of apical papillae as well as transformed oral squamous cancer stem cell (OSCSC) and Mia-Paca-2, poorly differentiated stem-like pancreatic tumors, resulting in their resistance to NK cell-mediated cytotoxicity. Induction of NK cell resistance and differentiation in the stem cells correlated with the increased expression of CD54, B7H1, and MHC class I, and mediated by the combination of membrane-bound or secreted IFN-γ and TNF-α from the NK cells since antibodies to both cytokines and not each one alone were able to inhibit differentiation or resistance to NK cells. Similarly, antibodies to both TNF-α and IFN-γ were required to prevent NK-mediated inhibition of cell growth, and restored the numbers of the stem cells to the levels obtained when stem cells were cultured in the absence of anergized NK cells. Interestingly, the effect of anti-IFN-γ antibody in the absence of anti-TNF-α antibody was more dominant for the prevention of increase in surface receptor expression since its addition abrogated the increase in CD54, B7H1, and MHC class I surface expression. Antibodies to CD54 or LFA-1 was unable to inhibit differentiation whereas antibodies to MHC class I but not B7H1 increased cytotoxicity of well-differentiated oral squamous carcinoma cells as well as OSCSCs differentiated by the IL-2 + anti-CD16 mAb-treated NK cells whereas it inhibited the cytotoxicity of NK cells against OSCSCs. Thus, NK cells may inhibit the progression of cancer by killing and/or differentiation of cancer stem cells, which severely halt cancer growth, invasion, and metastasis. © 2014 Tseng, Bui, Man, Cacalano and Jewett.


Xin H.-W.,U.S. National Cancer Institute | Ambe C.M.,U.S. National Cancer Institute | Hari D.M.,U.S. National Cancer Institute | Wiegand G.W.,U.S. National Cancer Institute | And 17 more authors.
Gut | Year: 2013

Objective: The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. Methods: We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. Results: LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-aktmurine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. Conclusions: Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.


Avital I.,Bon Secours Cancer Institute | Avital I.,Uniformed Services University of the Health Sciences | Brucher B.L.D.M.,Theodor Billroth Academy | Nissan A.,Rabin Medical Center | And 3 more authors.
Surgical Oncology Clinics of North America | Year: 2012

Upwards of 40% of patient with colorectal cancer develop peritoneal carcinomatosis (CRCPC). Of the 2500 patients reported in the literature, 1000 underwent cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), resulting in median survival of 22 to 63 months. However, level I data from prospective randomized trials are limited. Further trials are indicated to identify peritoneal carcinomatosis in at-risk patients early in the natural history of the disease and confirm the efficacy of multimodality therapy (CRS/HIPEC/systemic therapy) in those with CRCPC amenable to CRS in the modern era of novel targeted and cytotoxic systemic therapy. © 2012.


Duffy S.M.,Bon Secours Cancer Institute | Coyle T.E.,SUNY Upstate Medical University
Journal of Clinical Apheresis | Year: 2013

Introduction Bleeding risk because of thrombocytopenia in patients with thrombotic thrombocytopenic purpura (TTP) often causes concern during placement of the central venous catheter for plasma exchange. This perceived risk of bleeding often triggers prophylactic platelet transfusion; however, the risk of platelet transfusion is unknown. Methods Single institution review of bleeding episodes after catheter insertion in patients with suspected TTP. Results Fifty-five thrombocytopenic patients with presumed TTP underwent a total of 57 catheter insertion attempts. There were no major bleeding complications and no bleeding that required invasive intervention. Fourteen patients with a median platelet count of 12,000/μL were transfused with platelets prior to catheter placement. Five (35%) of the transfused patients had minor bleeding complications that did not require intervention. In the nontransfused group, 12 (28%) patients had minor bleeding that did not require invasive intervention and three patients experienced bleeding episodes that resolved after applying direct pressure. Eight (15%) patients died during admission. Mortality in the transfused group was 43% versus 5% in the nontransfused group. In general, patients receiving platelet transfusion prior to catheter insertion were more acutely ill. Conclusion There were no major bleeding complications associated with plasma exchange catheter insertion in thrombocytopenic patients with presumed TTP. In light of the uncertain risk of platelet transfusion in patients with TTP, it may be reasonable to forgo prophylactic platelet transfusion prior to catheter placement. © 2013 Wiley Periodicals, Inc.


Harmon J.F.,Bon Secours Cancer Institute
Journal of applied clinical medical physics / American College of Medical Physics | Year: 2013

The presence of air/fluid surrounding implantable devices used for partial breast irradiation may significantly impact dose coverage to at-risk tissue. Of the 67 total patients retrospectively evaluated for this study, 32 (48%) had greater than 1 cc volume of air/fluid extending outside of the strut-adjusted volume implant (SAVI) device surface and were selected for comparison of planning approaches. The planning approaches utilized two different definitions of PTV_EVAL. One definition of a PTV_EVAL (PTV_EVALSAVI) was based on expanding 1 cm beyond the SAVI device only while accounting for the air/fluid using the NSABP Protocol B-39/RTOG Protocol 0413. The second PTV_EVAL definition (PTV_EVALCAV) was based on expanding 1 cm beyond the cavity (SAVI device plus air/fluid volume). The results indicate use of the B-39 formalism to account for air/fluid displacing the PTV_EVAL may overestimate the dose coverage to the at-risk tissue, especially for large contiguous volumes of air/fluid. Using the SAVI device to optimize dose covering the PTV_EVALCAV volume surrounding the cavity improves dosimetric coverage to at-risk tissue by 11.3% and 8.7% for V100 and V90, respectively, while the average V150 and V200 indices for PTV_EVALCAV increased by 9.1 cc and 5.0cc, respectively, and the average maximum rib and skin doses increased by 11.1% and 6.1%, respectively. The maximum skin dose, rib dose, V150, and V200 all met the planning objectives despite any increase in these parameters.


Brucher B.L.D.M.,Theodor Billroth Academy | Brucher B.L.D.M.,International Consortium of Research Excellence of the Theodor Billroth Academy | Brucher B.L.D.M.,Bon Secours Cancer Institute | Jamall I.S.,Theodor Billroth Academy | And 2 more authors.
BMC Cancer | Year: 2014

Background: Carcinogenesis is widely thought to originate from somatic mutations and an inhibition of growth suppressors, followed by cell proliferation, tissue invasion, and risk of metastasis. Fewer than 10% of all cancers are hereditary; the ratio in gastric (1%), colorectal (3-5%) and breast (8%) cancers is even less. Cancers caused by infection are thought to constitute some 15% of the non-hereditary cancers. Those remaining, 70 to 80%, are called " sporadic," because they are essentially of unknown etiology. We propose a new paradigm for the origin of the majority of cancers. Presentation of hypothesis: Our paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. If we are correct, this paradigm would suggest that the majority of the findings in cancer genetics so far reported are either late events or are epiphenomena that occur after the appearance of the pre-cancerous niche.Testing the hypothesis: If, based on experimental and clinical findings presented here, this hypothesis is plausible, then the majority of findings in the genetics of cancer so far reported in the literature are late events or epiphenomena that could have occurred after the development of a PCN. Our model would make clear the need to establish preventive measures long before a cancer becomes clinically apparent. Future research should focus on the intermediate steps of our proposed sequence of events, which will enhance our understanding of the nature of carcinogenesis. Findings on inflammation and fibrosis would be given their warranted importance, with research in anticancer therapies focusing on suppressing the PCN state with very early intervention to detect and quantify any subclinical inflammatory change and to treat all levels of chronic inflammation and prevent fibrotic changes, and so avoid the transition from a normal cell to a cancer cell.Implication of the hypothesis: The paradigm proposed here, if proven, spells out a sequence of steps, one or more of which could be interdicted or modulated early in carcinogenesis to prevent or, at a minimum, slow down the progression of many cancers. © 2014 Brücher and Jamall; licensee BioMed Central Ltd.


Fowler C.B.,Baltimore Veterans Affairs Medical Center | Man Y.-G.,Bon Secours Cancer Institute | Mason J.T.,Baltimore Veterans Affairs Medical Center
Journal of Cancer | Year: 2014

Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) have been validated at the highest level of evidence as clinical biomarkers of prognosis in breast cancer. The American Society of Clinical Oncology recommends using uPA and PAI-1 levels in breast tumors for deciding whether patients with newly diagnosed node-negative breast cancer can forgo adjuvant chemotherapy. The sole validated method for quantifying uPA and PAI-1 levels in breast tumor tissue is a colorimetric ELISA assay that takes 3 days to complete and requires 100-300 mg of fresh or frozen tissue. In this study we describe a new assay method for quantifying PAI-1 levels in human breast tumor tissue. This assay combines pressure-cycling technology to extract PAI-1 from breast tumor tissue with a highly sensitive liposome polymerase chain reaction immunoassay for quantification of PAI-1 in the tissue extract. The new PAI-1 assay method reduced the total assay time to one day and improved assay sensitivity and dynamic range by >100, compared to ELISA. © Ivyspring International Publisher.


Avital I.,Bon Secours Cancer Institute | Stojadinovic A.,Bon Secours Cancer Institute | Wang H.,Zhejiang Sci-Tech University | Mannion C.,Hackensack University Medical Center | And 3 more authors.
Cancer Genomics and Proteomics | Year: 2014

It is a commonly held belief that adult stem cells represent the "seeds" for normal cellular replenishment and also for carcinogenesis. The identification and characterization of stem cells for clinical therapeutic applications, however, is extremely challenging for a number of reasons. Recently, our group and others have attempted to isolate stem cells using spheroids from fresh surgical specimens and utilize them for in vitro and in vivo studies. This mini-review summarizes the major technical steps of these methods along with the primary findings. Besides, it critically analyzes the advantages and limitations of the concept and technical approaches. Finally, this mini-review presents our thoughts on the potential future directions of stem cell isolation and cancer stem cell-related research and clinical applications.


Brucher B.L.D.M.,Theodor Billroth Academy | Brucher B.L.D.M.,International Consortium of Research Excellence of the Theodor Billroth Academy | Brucher B.L.D.M.,Bon Secours Cancer Institute | Jamall I.S.,Theodor Billroth Academy | And 2 more authors.
Cellular Physiology and Biochemistry | Year: 2014

The delineation of key molecular pathways has enhanced our knowledge of the biology of tumor microenvironment, tumor dissemination, and carcinogenesis. The complexities of cell-cell communication and the possibilities for modulation provide new opportunities for treating cancers. Cells communicate by direct and indirect signaling. Direct cell-cell communication involves both, self-self-communication (intracrine and autocrine), and adjacent communication with nearby cells (juxtacrine), which themselves are regulated by distinct pathways. Indirect intercellular communication involves local communication over short distances (paracrine and synaptic signaling) or over large distances via hormones (endocrine). The essential components of cell-cell communication involve communication junctions (Connexins, Plasmodesmata, Ion Channels, Chemical Synapses, and Pannexins), occluding junctions (Tight Junctions), and anchoring junctions (Adherens, Desmosomes, Focal Adhesions, and Hemidesmosomes). The communication pathways pass through junctions at physical cell-cell attachments, and they go, as well, through the extracellular matrix (ECM) via the different transmembrane adhesion proteins (Cadherins and Integrins). We have here reviewed cell-cell communication involving (1) the components of junctions and their dynamic interplay with the other aspects of communication, including (2) the tumor microenvironment and carcinogenesis, (3) coupling and migration, (4) the underlying cell-cell and sub-cellular communication mechanisms (signaling) of anticancer treatments, and finally, (5) aspects of recent research on cell-cell communication. © 2014 S. Karger AG, Basel.

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