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PubMed | The Surgical Center, University of California at Los Angeles, John Wayne Cancer Institute at Providence Saint Johns Health Center and Providence Saint Johns Health Center
Type: Journal Article | Journal: Journal of the American College of Surgeons | Year: 2016

Retrospective data indicate that immunoprofiling of T cell markers can be prognostic in colon cancer. Prospective T cell immunoprofiling of colon cancer has not been well defined for patients whose lymph nodes are ultrastaged.A prospective cohort was selected from patients enrolled in an ongoing phase II multicenter trial of nodal ultrastaging for colon cancer. Primary tumor specimens from 89 patients were analyzed by immunohistochemistry for the T cells CD3(+), CD4(+), CD8(+), and FOXP3(+). Lymphocyte populations were quantified with digital image analysis. Results were examined for their association with 5-year disease-free survival along with TNM stage and clinicopathologic variables.Longer disease-free survival was associated with higher CD3(+) counts at the invasive margin (IM) (p= 0.005), higher CD8(+) counts at the tumor center (TC) and IM (p= 0.002), a lower CD4(+)/CD8(+) ratio at the TC+IM (p= 0.027), and a higher CD8(+)/FOXP3(+) ratio at the TC+IM (p= 0.020). After multivariable analysis, CD8(+) at the TC+IM (p= 0.002), the CD8(+)/FOXP3(+) ratio at the TC+IM (p= 0.004), and the number of tumor-positive lymph nodes (p= 0.003) remained significant.This is the first prospective demonstration of the prognostic utility of immunoprofiling in colon cancer after nodal ultrastaging. Staging based on tumor immunoprofile can augment TNM staging and provide targets for specific immunotherapies.


Saria M.G.,John Wayne Cancer Institute At Providence Saint Johns Health Center | Kesari S.,John Wayne Cancer Institute
Clinical Journal of Oncology Nursing | Year: 2016

Background: Glioblastoma (GBM) is a highly aggressive astrocytoma with a dismal prognosis. Since 1976, only three chemotherapeutic agents have been approved for the treatment of GBM. Tumor-treating fields (TTFields) therapy, delivered via a noninvasive device, is a new therapy approved for use in patients with recurrent GBM and in combination with temozolomide for the treatment of newly diagnosed GBM. Objectives: This article reviews the mechanism of action and findings from preclinical and clinical studies supporting the use of TTFields for patients with newly diagnosed and recurrent GBM. Methods: This article provides an overview of published literature on the efficacy and safety of treating GBM with TTFields. Findings: For the first time in more than a decade, patients with GBM have a noninvasive treatment option that has been shown to increase progression-free survival and overall survival with minimal adverse events. © 2016 Oncology Nursing Society. All rights reserved.


Deutsch G.B.,John Wayne Cancer Institute At Providence Saint Johns Health Center | O'Connor V.,John Wayne Cancer Institute At Providence Saint Johns Health Center | Sim M.-S.,John Wayne Cancer Institute At Providence Saint Johns Health Center | Lee J.H.,John Wayne Cancer Institute At Providence Saint Johns Health Center | And 2 more authors.
Annals of Surgical Oncology | Year: 2015

Methods: The Surveillance, Epidemiology and End Results Program (SEER) database was used to identify 124,972 patients with gastric cancer between 2000 and 2010. Primary endpoints were 5-year disease-specific survival (DSS) and overall survival (OS). Analysis was performed on patients with ≥15 nodes evaluated. Multivariable regression with/without the inclusion of lymph node (LN) assessment and LN ratio were compared using the Akaike information criterion.Results: The number of patients included in the final analysis was 12,096. The proportion of patients with an adequate lymphadenectomy increased markedly from 27 % in 2000 to 52 % in 2010. Overall 5-year DSS and OS was 61.9 and 48.8 %, respectively, for patients with ≥15 nodes examined, versus 57.7 and 39.9 %, respectively, for those with <15 sampled nodes (p < 0.0001). In patients with ≥15 nodes evaluated, the addition of LN evaluation and LN ratio to the existing staging model improved its ability to predict 5-year DSS and OS (p < 0.0001). LN evaluation and LN ratio were comparable in their ability to supplement the existing AJCC 7th edition (AJCC7) staging system.Conclusion: The inclusion of a minimum 15-LN quality measure improves the prognostic ability of the AJCC7 staging system, without adding significant complexity.Background: The staging of gastric cancer has become increasingly complex. With an emerging 15-node quality measure and a revised American Joint Committee on Cancer (AJCC) staging system, we evaluated the need for more intricate staging systems to predict survival outcomes in gastric cancer. © 2014, Society of Surgical Oncology.


Ohta K.,John Wayne Cancer Institute at Providence Saint Johns Health Center | Hoshino H.,John Wayne Cancer Institute at Providence Saint Johns Health Center | Wang J.,John Wayne Cancer Institute at Providence Saint Johns Health Center | Ono S.,John Wayne Cancer Institute at Providence Saint Johns Health Center | And 5 more authors.
Oncotarget | Year: 2015

To assess the role of microRNAs (miR) in hepatocellular carcinoma (HCC), we performed comprehensive microRNA expression profiling using HCC cell lines and identified miR-93 as a novel target associated with HCC. We further verified miR-93 expression levels in advanced HCC tumors (n=47) by a direct PCR assay and found that elevated miR-93 expression level is significantly correlated with poor prognosis. Elevated miR-93 expression significantly stimulated in vitro cell proliferation, migration and invasion, and additionally inhibited apoptosis. We confirmed that miR-93 directly bound with the 3' untranslated regions of the tumorsuppressor genes PTEN and CDKN1A, respectively, and inhibited their expression. As a result of this inhibition, the c-Met/PI3K/Akt pathway activity was enhanced. IHC analysis of HCC tumors showed significant correlation between c-Met protein expression levels and miR-93 expression levels. Knockdown of c-Met inhibited the activation of the c-Met/PI3K/Akt pathway regardless of hepatocyte growth factor (HGF) treatment, and furthermore reduced the expression of miR-93 in these HCC cells. miR-93 also rendered cells to be more sensitive to sorafenib and tivantinib treatment. We concluded that miR-93 stimulated cell proliferation, migration, and invasion through the oncogenic c-Met/PI3K/Akt pathway and also inhibited apoptosis by directly inhibiting PTEN and CDKN1A expression in human HCC.


PubMed | University of California at San Diego and John Wayne Cancer Institute at Providence Saint Johns Health Center
Type: Review | Journal: Nature reviews. Neurology | Year: 2016

Standard treatment of primary and metastatic brain tumours includes high-dose megavoltage-range radiation to the cranial vault. About half of patients survive >6 months, and many attain long-term control or cure. However, 50-90% of survivors exhibit disabling cognitive dysfunction. The radiation-associated cognitive syndrome is poorly understood and has no effective prevention or long-term treatment. Attention has primarily focused on mechanisms of disability that appear at 6 months to 1 year after radiotherapy. However, recent studies show that CNS alterations and dysfunction develop much earlier following radiation exposure. This finding has prompted the hypothesis that subtle early forms of radiation-induced CNS damage could drive chronic pathophysiological processes that lead to permanent cognitive decline. This Review presents evidence of acute radiation-triggered CNS inflammation, injury to neuronal lineages, accessory cells and their progenitors, and loss of supporting structure integrity. Moreover, injury-related processes initiated soon after irradiation could synergistically alter the signalling microenvironment in progenitor cell niches in the brain and the hippocampus, which is a structure critical to memory and cognition. Progenitor cell niche degradation could cause progressive neuronal loss and cognitive disability. The concluding discussion addresses future directions and potential early treatments that might reverse degenerative processes before they can cause permanent cognitive disability.


PubMed | University of California at San Diego and John Wayne Cancer Institute at Providence Saint Johns Health Center
Type: Journal Article | Journal: Oncotarget | Year: 2016

Oligodendrocyte lineage transcription factor 2 (OLIG2) plays a pivotal role in glioma development. Here we conducted a comprehensive study of the critical gene regulatory networks involving OLIG2. These include the networks responsible for OLIG2 expression, its translocation to nucleus, cell cycle, epigenetic regulation, and Rho-pathway interactions. We described positive feedback loops including OLIG2: loops of epigenetic regulation and loops involving receptor tyrosine kinases. These loops may be responsible for the prolonged oncogenic activity of OLIG2. The proposed schemes for epigenetic regulation of the gene networks involving OLIG2 are confirmed by patient survival (Kaplan-Meier) curves based on the cancer genome atlas (TCGA) datasets. Finally, we elucidate the Coherent-Gene Modules (CGMs) networks-framework of OLIG2 involvement in cancer. We showed that genes interacting with OLIG2 formed eight CGMs having a set of intermodular connections. We showed also that among the genes involved in these modules the most connected hub is EGFR, then, on lower level, HSP90 and CALM1, followed by three lower levels including epigenetic genes KDM1A and NCOR1. The genes on the six upper levels of the hierarchy are involved in interconnections of all eight CGMs and organize functionally defined gene-signaling subnetworks having specific functions. For example, CGM1 is involved in epigenetic control. CGM2 is significantly related to cell proliferation and differentiation. CGM3 includes a number of interconnected helix-loop-helix transcription factors (bHLH) including OLIG2. Many of these TFs are partially controlled by OLIG2. The CGM4 is involved in PDGF-related: angiogenesis, tumor cell proliferation and differentiation. These analyses provide testable hypotheses and approaches to inhibit OLIG2 pathway and relevant feed-forward and feedback loops to be interrogated. This broad approach can be applied to other TFs.


Billar J.A.,John Wayne Cancer Institute At Providence Saint Johns Health Center | Sim M.S.,John Wayne Cancer Institute At Providence Saint Johns Health Center | Chung M.,John Wayne Cancer Institute At Providence Saint Johns Health Center
Annals of Surgical Oncology | Year: 2014

Background: Radiotherapy (RT) reduces local recurrence after breast-conserving surgery (BCS) for breast cancer, but under-utilization of RT has been reported. Accelerated partial-breast irradiation (PBI) improves RT accessibility, but it is uncertain if this has improved RT utilization.Methods: The Surveillance, Epidemiology and End Results registry was used to identify women who underwent BCS for stage 0 or 1 breast cancer from 2000 to 2009. Temporal trends in RT utilization and RT modality were determined. Chi-square analysis and multivariate logistic regression identified predictors of RT utilization and modality.Results: Of 180,219 study patients, 131,343 (73 %) received RT; 123,703 (94 %) of RT recipients received whole-breast irradiation (WBI) and 6,251 (5 %) received PBI. PBI rates increased dramatically during the study period (0.32 % in 2000 vs. 6.5 % in 2009), but overall RT utilization remained relatively stable because of a decline in WBI (69.8 % in 2000 vs. 62.4 % in 2009). RT utilization was unchanged in rural counties, and declined for women <40 and ≥70 years of age, and for Native American, Asian and Hispanic patients. White and Black women used PBI most frequently (4 % each) and were the only race groups with improved RT utilization over time. Predictors of RT usage included age, race, marital status, tumor size, grade, hormone receptor status, lymph node evaluation, geographic region, metropolitan status, education, and employment status.Conclusions: Women who undergo RT are opting for PBI more frequently, but the increased use of this modality has not improved overall RT utilization for patients with early-stage breast cancer. © 2014, Society of Surgical Oncology.


Huang S.K.,John Wayne Cancer Institute at Providence Saint Johns Health Center | Hoon D.S.B.,John Wayne Cancer Institute at Providence Saint Johns Health Center
Molecular Oncology | Year: 2016

Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective. © 2015 Federation of European Biochemical Societies.


PubMed | John Wayne Cancer Institute at Providence Saint Johns Health Center
Type: Journal Article | Journal: The American surgeon | Year: 2016

The impact on survival of a second primary melanoma (SPM) is unclear. We used our melanoma centers database to examine clinicopathologic risk factors and outcomes of stage 0 to IV cutaneous melanoma in patients with one versus two primaries. Among 12,325 patients with primary melanoma, 969 (7.86%) developed SPM. SPMs were significantly thinner than autologous primary melanomas (P = 0.01), and 451 SPM patients had better overall and melanoma-specific survival than 451 prognostically matched non-SPM patients (P < 0.0001 and 0.0001, respectively) at a median follow-up of 142.37 months. Patients with cutaneous melanoma are at high risk for development of SPM, but the development of SPM does not seem to impair survival.


PubMed | John Wayne Cancer Institute at Providence Saint Johns Health Center
Type: Journal Article | Journal: Clinical journal of oncology nursing | Year: 2016

Glioblastoma (GBM) is a highly aggressive astrocytoma with a dismal prognosis. Since 1976, only three chemotherapeutic agents have been approved for the treatment of GBM. Tumor-treating fields (TTFields) therapy, delivered via a noninvasive device, is a new therapy approved for use in patients with recurrent GBM and in combination with temozolomide for the treatment of newly diagnosed GBM.This article reviews the mechanism of action and findings from preclinical and clinical studies supporting the use of TTFields for patients with newly diagnosed and recurrent GBM.This article provides an overview of published literature on the efficacy and safety of treating GBM with TTFields.For the first time in more than a decade, patients with GBM have a noninvasive treatment option that has been shown to increase progression-free survival and overall survival with minimal adverse events.

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