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Richmond, VA, United States

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.

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.

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.

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.

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.

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