Macrophage-mediated trogocytosis can kill cancer cells

Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fc receptor (FcR)-mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is pro-tumorigenic. In the current study we demonstrate that persistent trogocytic attack results in the killing of HER2-overexpressing breast cancer cells. Further, antibody engineering to increase FcR interactions enhances this tumoricidal activity. These studies extend the complex repertoire of activities of macrophages to trogocytic-mediated cell death of HER2-overexpressing target cells and have implications for the development of effective antibody-based therapies.

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Comparison of Eligibility Criteria Between Protocols, Registries, and Publications of Cancer Clinical Trials

Trial registration and public accessibility of appended or published protocols of phase III randomized clinical trials (RCTs) allow comparison of reported research with essential aspects of trial design. We determined how eligibility criteria of participants specified in protocols were described in trial registries and articles of 255 cancer RCTs published in leading journals. The mean proportion of matching eligibility criteria between protocols and publications per trial (the primary endpoint) was 44.0% (95% confidence interval [CI] = 40.8% to 47.3%). Almost all discrepancies in eligibility criteria (96.7%, 95% CI = 96.1% to 97.3%) suggested to readers of articles that a broader study population was included. The mean proportion of matching eligibility criteria between protocols and registries was 72.9% (95% CI = 68.2% to 77.7%, the secondary endpoint). We conclude that there are substantial differences in eligibility criteria between trial protocols, registries and articles. Inaccurate reporting of eligibility criteria may prevent appropriate assessment of the applicability of trial results.

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p110{alpha} inhibition alters PanNETs progression

Purpose: Mutations in the PI3-kinase (PI3K) pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacological intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown Experimental Design: In the present study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α selective (GDC-0326) inhibitors and isoform specific PI3K kinase-dead mutant mice Results: Human and mouse PanNETs showed enhanced pAKT, pPRAS40 and pS6 positivity compared to normal tissue. While treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node (LN) metastasis compared to vehicle treated mice. We also demonstrated that tumor and stromal cells are implicated in the anti-tumor activity of GDC-0326 in RIP1-Tag2 tumors Conclusions: Our data provide a rationale for p110α selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis.

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PD-1 Pathway Blockade in EGFR-mutant and ALK-positive NSCLC

Purpose: PD-1 inhibitors are established agents in the management of non-small cell lung cancer (NSCLC); however, only a subset of patients derives clinical benefit. To determine the activity of PD-1/PD-L1 inhibitors within clinically-relevant molecular subgroups, we retrospectively evaluated response patterns among EGFR-mutant, ALK-positive, and EGFR wild-type/ALK-negative patients. Experimental Design: We identified 58 patients treated with PD-1/PD-L1 inhibitors. Objective response rates (ORRs) were assessed using RECIST v1.1. PD-L1 expression and CD8+ tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry. Results: Objective responses were observed in 1/28 (3.6%) EGFR-mutant or ALK-positive patients versus 7/30 (23.3%) EGFR wild-type and ALK-negative/unknown patients (P = 0.053). The ORR among never- or light- ({less than or equal to}10 pack years) smokers was 4.2% versus 20.6% among heavy smokers (P = 0.123). In an independent cohort of advanced, EGFR-mutant (N=68) and ALK-positive (N=27) patients, PD-L1 expression was observed in 24%/16%/11% and 63%/47%/26% of pre-tyrosine kinase inhibitor (TKI) biopsies using cutoffs of {greater than or equal to}1%, {greater than or equal to}5% and {greater than or equal to}50% tumor cell staining, respectively. Among EGFR-mutant patients with paired, pre- and post-TKI resistant biopsies (N=57), PD-L1 expression levels changed after resistance in 16 (28%) patients. Concurrent PD-L1 expression ({greater than or equal to}5%) and high levels of CD8+ TILs (grade {greater than or equal to}2) were observed in only 1 pre-treatment (2.1%) and 5 resistant (11.6%) EGFR-mutant specimens, and was not observed in any ALK-positive, pre- or post-TKI specimens. Conclusions: NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8+ TILs within the tumor microenvironment may underlie these clinical observations.

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MELK confers radioresistance in TNBC

Purpose: While effective targeted therapies exist for estrogen receptor-positive and HER2-positive breast cancer, no such effective therapies exist for triple-negative breast cancer (TNBC), thus it is clear that additional targets for radiosensitization and treatment are critically needed. Experimental Design: Expression microarrays, qRT-PCR, and western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition. The effect of MELK knockdown on DNA damage repair kinetics was determined using H2AX staining. The in vivo effect of MELK knockdown on radiosensitivity was performed using mouse xenograft models. Kaplan-Meier analysis was used to estimate local control and survival information and a Cox proportional hazards model was constructed to identify potential factors impacting local recurrence-free survival. Results: : MELK expression is significantly elevated in breast cancer tissues compared to normal tissue as well as in TNBC compared to non-TNBC. MELK RNA and protein expression is significantly correlated with radioresistance in breast cancer cell lines. Inhibition of MELK (genetically and pharmacologically) induces radiation sensitivity in vitro and significantly delayed tumor growth in vivo in multiple models. Kaplan-Meier survival and multivariable analyses identify increasing MELK expression as being the strongest predictor of radioresistance and increased local recurrence in multiple independent datasets. Conclusions: Here, we identify MELK as a potential biomarker of radioresistance and target for radiosensitization in TNBC. Our results support the rationale for developing clinical strategies to inhibit MELK as a novel target in TNBC.

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IMA950 Phase I Trial Final Results

PURPOSE: To perform a two-cohort, phase 1 safety and immunogenicity study of IMA950 in addition to standard chemo-radiotherapy (CRT) and adjuvant temozolomide in patients with newly diagnosed glioblastoma (GBM). IMA950 is a novel GBM specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAPs), identified on human leukocyte antigen (HLA) surface receptors in primary human GBM tissue. EXPERIMENTAL DESIGN: Patients were HLA A*02 positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus GM-CSF over a 24 week period, beginning 7-14 days prior to initiation of CRT (Cohort 1) or 7 days post CRT (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP specific T cell immune responses determined. Secondary observations included progression-free survival (PFS), pre-treatment regulatory T-cell (Treg) levels and the effect of steroids on T-cell responses. RESULTS: Forty five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced Grade 3 dose limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pre-treatment Treg levels on IMA950 immunogenicity was observed and steroids did not affect TUMAP responses. PFS was 74% at 6 months and 31% at 9 months. CONCLUSION: IMA950 plus GM-CSF was well tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged.

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Characteristics and Prognostic Analysis of 69 Patients With Pulmonary Sarcomatoid Carcinoma

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare malignancy. Methods: A total of 69 patients with PSC treated at a single institution in southern China with long-term follow-up were evaluated in this study. We analyzed the clinical characteristics, immunohistochemical profiles, epidermal growth factor receptor mutation status, K-RAS mutation status, treatments, and prognosis. Results: PSC mainly occurred in young male patients with a history of smoking. Most patients received multimodality treatments and the majority had early-stage disease. The median survival time was 19.1 months, and the 5-year survival rate was 17.4%. The patients without distant metastasis, with normal or higher body mass index (≥18.5), with normal hemoglobin, with smaller tumor size (≤4 cm), and those who received complete resection had significantly better overall survival (P

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The Impact of Positive Margins on Outcome Among Patients With Gastric Cancer Treated With Radiation

Objectives: Positive surgical margins have been associated with worse outcomes in gastric cancer patients. We evaluated the impact of positive margins in a modern cohort treated with radiotherapy. Methods: We performed a multi-institutional retrospective analysis of patients treated from 1998 through 2010. All underwent definitive surgery and were followed up for recurrence and survival. We assessed associations with positive margins using the log-rank tests and Cox proportional hazard models. Results: We identified 91 patients with a median follow-up of 42 months. Seven received radiation before surgery; the remainder were treated postoperatively. Epirubicin-based chemotherapy was given to 8 patients perioperatively and 25 postoperatively. Nineteen had positive margins (21%), including 25% of patients who received chemotherapy perioperatively. All patients who received neoadjuvant radiotherapy had negative margins. There were 41 recurrences and 44 deaths. Positive margins were associated with increased recurrence risk after adjusting for other factors (hazard ratio=2.8, P=0.01). In addition, median survival with positive margins was 31 months as compared with 77 months after complete resection (P=0.13). Conclusions: Positive margins were associated with recurrence despite aggressive multimodality therapy including radiotherapy and the selective use of chemotherapy. Thus, additional consideration is warranted for strategies such as neoadjuvant chemoradiation intended to facilitate complete resection.

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Outcome of Transplant-fallout Patients With Unresectable Cholangiocarcinoma

Objectives: The aim of this was to determine survival after starting neoadjuvant therapy for patients who became ineligible for orthotopic liver transplantation (OLT). Methods and Materials: Since January 1993, 215 patients with unresectable cholangiocarcinoma began treatment with planned OLT. Treatment included external-beam radiation therapy (EBRT) with fluorouracil, bile duct brachytherapy, and postradiotherapy fluorouracil or capecitabine before OLT. Adverse findings at the staging operation, death, and other factors precluded OLT in 63 patients (29%), of whom 61 completed neoadjuvant chemoradiation. Results: By October 2012, 56 (89%) of the 63 patients unable to undergo OLT had died. Twenty-two patients (35%) became ineligible for OLT before the staging operation, 38 (60%) at the staging operation, and 3 (5%) after staging. From the date of diagnosis, median overall survival was 12.3 months. Survival was 17% at 18 months and 7% at 24 months. Median survival after fallout was 6.8 months. Median survival after the staging operation was 6 months. Two patients lived for 3.7 and 8.7 years before dying of cancer or liver failure caused by persistent biliary stricture at the site of the original cancer, respectively. Univariate analysis showed that time from diagnosis to fallout correlated with overall survival (P=0.04). Conclusions: In highly selected patients initially suitable for OLT, the mortality rate for cholangiocarcinoma was high in patients who became ineligible for OLT. Their survival, however, was comparable to expected survival for patients with locally advanced or metastatic disease treated with nontransplant therapies. The most common reason for patient fallout was adverse findings at the staging operation.

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High-circulating Tie2 Is Associated With Pathologic Complete Response to Chemotherapy and Antiangiogenic Therapy in Breast Cancer

Introduction: Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in breast cancer. Research in antiangiogenic cancer treatment has been marked by the development of the monoclonal antibody bevacizumab, which targets VEGF in many solid tumors. As patients do not equally benefit from bevacizumab, it has become necessary to define the profile of patients who will benefit from the drug. Materials and Methods: We have conducted a prospective phase II study in 39 patients using bevacizumab in breast cancer in the neoadjuvant setting, and found improved pathologic complete response (pCR) when bevacizumab was added to chemotherapy in patients with hormone receptor negative and invasive ductal carcinoma. Blood samples were collected at baseline and serially while patients were on treatment. Circulating angiogenesis-related proteins angiopoietin (ANG)1, ANG2, basic fibroblast growth factor, IL-1a, matrix metalloproteinase 9, platelet derived growth factor - BB, platelet endothelial cell adhesion molecule -1, Tie2, VEGF, and vascular endothelial growth factor receptor 2 were measured at baseline and during treatment. This correlative study was conducted to identify specific serum angiogenic factor profiles that might be associated with pCR in the neoadjuvant setting in breast cancer patients receiving bevacizumab and chemotherapy. Results: Elevated baseline serum Tie2 and basic fibroblast growth factor were associated with pCR in response to this combination. Changes in serum levels of these proteins were seen during treatment but were not significantly different between the pCR and non-pCR groups. Conclusions: Baseline-circulating Tie2 levels may help distinguish patients who will have pCR from those who will not and may form the basis for future development of antiangiogenic therapy in breast cancer. Larger studies are needed to validate these findings. ClinicalTrials.gov Identifier: NCT00203502.

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Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors

Objectives: Pazopanib is a tyrosine kinase inhibitor predominantly acting on tumor endothelium, and ixabepilone is a semisynthetic analog of epothilone B that promotes microtubule stabilization inducing tumor and tumor endothelial cell apoptosis. The purpose of this study was to determine the optimal tolerated dose (OTD) of the combination of pazopanib and ixabepilone for the treatment of metastatic previously treated solid tumors. Methods: Dose escalation started at 32 mg/m2 of ixabepilone and increased to 40 mg/m2. Pazopanib was administered initially at 400 mg and escalated at 200 mg increments up to 800 mg. Pharmacokinetic analysis assessed effect of ixabepilone on pazopanib metabolism. Correlative studies evaluated changes in angiogenic cytokines. Results: Thirty-one patients (20 male and 11 female; median age, 58 y) with ECOG PS of 0 or 1 were enrolled. Three patients had dose-limiting toxicities (fatigue and neutropenia) at dose level 2 (ixabepilone 40 mg/m2 and pazopanib 400 mg), and therefore the ixabepilone dose was decreased (32 mg/m2) before escalating pazopanib to levels 3 and 4. One patient had a dose-limiting toxicity (thrombocytopenia) at dose level 4 (ixabepilone 32 mg/m2 and pazopanib 800 mg). Dose level 3 was determined to be the OTD (pazopanib 600 mg and ixabepilone 32 mg/m2). The most common toxicities were cytopenias. A significant decrease in the level of sE-selectin was associated with improvement in progression free survival. Conclusions: The OTD for combination of pazopanib and ixabepilone was established. There was no impact of ixabepilone on pazopanib pharmacokinetics. The relationship between sE-selectin and progression free survival warrants further investigation.

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Population-based Analysis of Treatment and Survival in Women Presenting With Brain Metastasis at Initial Breast Cancer Diagnosis

Purpose: Brain metastasis at initial breast cancer diagnosis is rare. This study aims to evaluate the clinical characteristics of these patients and identify prognostic and treatment factors associated with improved survival. Methods: Subjects were 35 women referred from 1996 to 2005 with newly diagnosed breast cancer with synchronous brain metastasis. Overall survival (OS) and brain progression-free survival were examined using Kaplan-Meier methods and compared between subgroups with different clinicopathologic and treatment characteristics using log-rank tests. Results: Median age was 65 years. Whole-brain radiotherapy (WBRT) alone was used in 25 patients, surgical resection and postoperative WBRT in 5 patients, and no or unknown treatment in 5 patients. Patients who underwent cranial resection were more likely to have solitary brain metastasis (P=0.003) and no visceral involvement (P=0.006). Overall, median OS was 6.8 months and median brain progression-free survival was 6.5 months (range, 0.7 to 54 mo). Median OS were 15 months with surgery and postoperative WBRT, 5 months with WBRT alone, and 3 months with no brain treatment. Longer OS was observed with age below 65 years versus 65 years and above (11 vs. 5 mo, P=0.046), 0 to 1 versus ≥2 sites of extracranial metastasis (10 vs. 3 mo, P=0.047), and diagnosis from 2001 to 2005 versus 1996 to 2000 (10 vs. 3 mo, P=0.018). A trend toward improved OS was observed in patients with no visceral involvement (11 vs. 4 mo, P=0.09). Conclusions: In this unique cohort presenting with breast cancer and synchronous brain metastasis, longer survival were observed with young age, limited extracranial metastasis, and no visceral disease. These characteristics may be used to select candidates for more aggressive treatment.

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The Impact of Cancer on the Clinical Outcome of Patients After Inferior Vena Cava Filter Placement: A Retrospective Cohort Study

Objectives: Inferior vena cava (IVC) filters are placed to prevent pulmonary embolism, however, some studies have suggested that IVC filters are associated with exacerbated risks of deep vein/IVC thrombosis in cancer patients. The purpose of this study is to determine if cancer patients develop higher than expected rates of venous thromboembolism complications after filter placement compared with noncancer patients. Materials and Methods: A retrospective cohort study of consecutive patients who received filters (2002 to 2006) at Johns Hopkins was conducted. Exposures and outcomes were obtained by chart review. Relative risks (RR, 95% confidence interval [CI]) for outcomes in cancer versus noncancer patients were estimated using multistate models. Results: The cohort included 702 patients—246 with cancer and 456 without cancer. Cancer patients were older, more likely to be white and have filters placed for contraindications to anticoagulation (P

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Does Race Influence Health-related Quality of Life and Toxicity Following Proton Therapy for Prostate Cancer?

Objective: This matched-paired analysis explores disparities in health-related quality of life (QOL) and common toxicities between African American (AA) and white patients following proton therapy for prostate cancer at our institution. Materials and Methods: A total of 1536 men with clinically localized prostate cancer were treated from 2006 to 2009 with definitive proton therapy to a median dose of 78 Gy +/− androgen deprivation therapy. A cohort of 92 consecutively treated AA men was matched to a cohort of 92 white men on the basis of National Comprehensive Cancer Network risk category and age. The 2 groups were compared with regard to comorbidities, demographics, and treatment regimen. Differences in genitourinary and gastrointestinal (GI) toxicity according to the Common Terminology Criteria for Adverse Events scale and QOL data from the Expanded Prostate Index Composite 26-question questionnaire were reported. Results: Median follow-up was 2.1 years. Baseline patient and treatment characteristics were similar between the 2 groups with the exception of prostate-specific antigen ≥10 (32% for AAs vs. 20% for whites; P=0.068) and use of androgen deprivation therapy (26% for AAs vs. 21% for whites; P=0.38). No difference in Expanded Prostate Index Composite 26-question sexual summary, urinary incontinence, urinary obstruction, or bowel summary scores was detected between the 2 groups, nor was there a difference in grade 2 or higher GI toxicity (P=0.45). AAs had a statistically nonsignificant higher absolute incidence of late grade 3 genitourinary toxicity (4.4% vs. 0%; P=0.12). Conclusions: After 2 years, there were no disparities in health-related QOL, physician-reported Common Terminology Criteria for Adverse Events GI toxicity, or biochemical relapse. Longer follow-up is needed to confirm these findings.

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The Role of MRI in the Follow-up of Women Undergoing Breast-conserving Therapy

Objectives: Breast-conserving therapy (BCT) represents a standard of care in the management of breast cancer. However, unlike mastectomy, women treated with BCT require follow-up imaging of the treated breast as well as the contralateral breast as part of posttreatment surveillance. Traditionally, surveillance has consisted of clinical exams and mammograms. However, magnetic resonance imaging (MRI) has emerged as a breast imaging technique utilized as part of high-risk screening programs as well as part of the initial diagnosis and workup of women considered for BCT. At this time, the role of MRI as part of follow-up for women treated with BCT remains unclear. Methods: A systematic review was performed to evaluate the role of MRI following BCT. Results: Although there is no randomized evidence supporting the routine use of MRI in surveillance post-BCT, a review of the literature demonstrates that MRI (1) has increased sensitivity as compared with mammography to detect recurrences, and (2) can help evaluate mammographic abnormalities before biopsy and/or surgery. Conclusions: In patients with higher risk of local recurrence, surveillance with MRI may represent an effective surveillance strategy though subgroups benefiting have not been identified nor has the impact on quality of life and cost been evaluated.

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Analytical validity of a microRNA-based assay for diagnosing indeterminate thyroid FNA smears from routinely prepared cytology slides

BACKGROUND

The majority of thyroid nodules are diagnosed using fine-needle aspiration (FNA) biopsies. The authors recently described the clinical validation of a molecular microRNA-based assay, RosettaGX Reveal, which can diagnose thyroid nodules as benign or suspicious using a single stained FNA smear. This paper describes the analytical validation of the assay.

METHODS

More than 800 FNA slides were tested, including slides stained with Romanowsky-type and Papanicolaou stains. The assay was examined for the following features: intranodule concordance, effect of stain type, minimal acceptable RNA amounts, performance on low numbers of thyroid cells, effect of time since sampling, and analytical sensitivity, specificity, and reproducibility.

RESULTS

The assay can be run on FNA slides for which as little as 1% of the cells are thyroid epithelial cells or from which only 5 ng of RNA have been extracted. Samples composed entirely of blood failed quality control and were not classified. Stain type did not affect performance. All slides were stored at room temperature. However, the length of time between FNA sampling and processing did not affect assay performance. There was a high level of concordance between laboratories (96%), and the concordance for slides created from the same FNA pass was 93%.

CONCLUSIONS

The microRNA-based assay was robust to various physical processing conditions and to differing sample characteristics. Given the assay's performance, robustness, and use of routinely prepared FNA slides, it has the potential to provide valuable aid for physicians in the diagnosis of thyroid nodules. Cancer Cytopathol 2016;000:000-000. © 2016 Rosetta Genomics. Cancer Cytopathology published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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Patient-Reported Outcomes of a Multi-Center Phase II Study Investigating Gemcitabine and Stereotactic Body Radiotherapy in Locally Advanced Pancreatic Cancer

Publication date: Available online 25 May 2016
Source:Practical Radiation Oncology
Author(s): Avani D. Rao, Elizabeth A. Sugar, Daniel T. Chang, Karyn A. Goodman, Amy Hacker-Prietz, Lauren M. Rosati, Laurie Columbo, Eileen O'Reilly, George A. Fisher, Lei Zheng, Jonathan S. Pai, Mary E. Griffith, Daniel A. Laheru, Christine A. Iacobuzio-Donahue, Christopher L. Wolfgang, Albert Koong, Joseph M. Herman
PurposeWe previously reported clinical outcomes and physician-reported toxicity of gemcitabine and hypofractionated stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (LAPC). Here we prospectively investigate the impact of gemcitabine and SBRT on patient-reported quality of life (QoL).Materials and MethodsForty-nine LAPC patients received 33Gy SBRT (6.6Gy daily fractions) upfront or after ≤3 doses of gemcitabine (1000mg/m²) followed by gemcitabine until progression. European Organization for Research and Treatment of Cancer QoL core cancer (EORTC QLQ-C30) and pancreatic cancer-specific (EORTC QLQ-PAN26) questionnaires were administered to patients pre-SBRT and at 4–6 weeks (1FUP) and 4months (2FUP) post-SBRT. Changes in QoL scores were deemed clinically relevant if median changes were at least 5 points in magnitude.ResultsForty-three (88%) patients completed pre-SBRT questionnaires. Of these, 88% and 51% completed questionnaires at 1FUP and 2FUP, respectively. There was no change in global QoL from pre-SBRT to 1FUP (p=0.17) or 2FUP (p>0.99). Statistical and clinical improvements in pancreatic pain (p=0.001) and body image (p=0.007) were observed from pre-SBRT to 1FUP.Patients with 1FUP and 2FUP questionnaires reported statistically and clinically improved body image (p=0.016) by 4months. Although pancreatic pain initially demonstrated statistical and clinical improvement (p=0.020), scores returned to enrollment levels by 2FUP (p=0.486). A statistical and clinical decline in role functioning (p=0.002) was observed in patients at 2FUP.ConclusionsGlobal QoL scores are not reduced with gemcitabine and SBRT. In this exploratory analysis, patients experience clinically relevant short-term improvements in pancreatic cancer-specific symptoms. Previously demonstrated acceptable clinical outcomes combined with these favorable QoL data indicate that SBRT can be easily integrated with other systemic therapies and may be a potential standard of care option in patients with LAPC.



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An Unanticipated Question

Publication date: Available online 25 May 2016
Source:Practical Radiation Oncology
Author(s): Joel B. Wolowelsky




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A new mouse model of acute adult T-cell leukemia generated by transplantation of AKT, BCLxL, and HBZ-transduced T cells

Abstract

Adult T-cell leukemia/lymphoma (ATL) develops in human T-cell leukemia virus type 1 (HTLV-1) carriers. Although the HTLV-1-encoded HBZ gene is critically involved, HBZ alone is insufficient, and additional, cooperative "hits" are required for the development of ATL. Candidate cooperative hits are being defined, but methods to rapidly explore their roles in ATL development in collaboration with HBZ are lacking. Here, we present a new mouse model of acute type ATL that can be generated rapidly by transplanting in vitro-induced T cells that have been retrovirally transduced with HBZ and two cooperative genes, BCLxL and AKT, into mice. Co-transduction of HBZ and BCLxL/AKT allowed these T cells to grow in vitro in the absence of cytokines (Flt3-ligand and IL-7), which did not occur with any two-gene combination. Although transplanted T cells were a mixture of cells transduced with different combinations of the genes, tumors that developed in mice were composed of HBZ/BCLxL/AKT triply transduced T cells, showing the synergistic effect of the three genes. The genetic/epigenetic landscape of ATL has only recently been elucidated, and the roles of additional "hits" in ATL pathogenesis remain to be explored. Our model provides a versatile tool to examine the roles of these hits, in collaboration with HBZ, in the development of acute ATL.

This article is protected by copyright. All rights reserved.

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Sex disparities in use of chemotherapy and survival in patients with advanced bladder cancer

BACKGROUND

Women with advanced bladder cancer have inferior survival compared with men. However, women treated on clinical trials do not appear to have a survival disadvantage. Less frequent administration of systemic chemotherapy in women with advanced bladder cancer may contribute to their inferior survival.

METHODS

The authors identified patients diagnosed with stage IV bladder cancer from 1998 through 2010 using the National Cancer Data Base, a national outcomes database that includes 70% of all newly diagnosed cancer cases in the United States. Sex differences in demographics, systemic chemotherapy administration, and overall survival (OS) were compared.

RESULTS

A total of 23,981 patients were identified (35% of whom were female). Compared with men, women were older, more likely to be black, and less likely to be insured (P<.01 for all). The Charlson-Deyo comorbidity score did not differ between men and women. Women were less likely to receive systemic chemotherapy than men (45% vs 52%; adjusted relative risk, 0.91 [95% confidence interval (95% CI), 0.88-0.94]). Women had a lower median OS compared with men (8.0 months [95% CI, 7.7-8.3 months] vs 9.8 months [95% CI, 9.5-10.0 months]; P<.001). OS remained lower for women on multivariable analysis, even after adjusting for the administration of systemic chemotherapy (hazard ratio for death, 1.11 [95% CI, 1.08-1.15]).

CONCLUSIONS

Women are less likely than men to receive systemic chemotherapy for advanced bladder cancer and this difference may partially account for the poorer OS observed in women. However, OS remains lower in women independent of chemotherapy use, and may be related to unmeasured comorbidities, functional status, or tumor biology. Cancer 2016. © 2016 American Cancer Society.

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Mind the gap: What is driving the survival disparity between the sexes in bladder cancer?

Precis Bladder cancer is well known to preferentially afflict men. However, women are significantly more likely to die of the disease even when corrected for stage, tumor characteristics, and age. In this issue of Cancer, Rose and colleagues highlight concerning disparities in bladder cancer treatment and outcomes between the sexes.

See also pages 000–000.

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Issue Information - Ed Board

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Oncologic reconstruction of the hand and upper extremity: Maximizing functional outcomes

Upper extremity malignancies have the potential to create significant functional impairment, and as such represent an opportunity for collaborative reconstruction to minimize potential morbidity.

Given the increased complexity and array of potential reconstruction solutions, functional limb preservation is overwhelmingly and increasingly successful in appropriately selected patients. The purpose of this review is to familiarize the reader with the general functional considerations of the upper extremity, review major reconstructive options, and present a general algorithm for reconstruction and maintenance of function. J. Surg. Oncol. 2016;113:946–954. © 2016 Wiley Periodicals, Inc.

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Issue Information - TOC

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State-of-the-art reconstruction of midface and facial deformities

Oncologic resection involving the midface results in potentially disfiguring and challenging defects for the reconstructive surgeon. As with any defect, restoration of form and function is critical, but is particularly difficult in the midface, which is paramount to a patient's physical appearance and identify, as well as the patient's ability to breath, speak, see, and eat. Here, we present an algorithmic approach for optimizing outcomes in midfacial reconstruction utilizing the state-of-the-art reconstructive techniques. J. Surg. Oncol. 2016;113:962–970. © 2016 Wiley Periodicals, Inc.

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The impact of the revolution in hepatitis C treatment on hepatocellular carcinoma

Treatment with direct-acting anitiviral agents has revolutionized the treatment of chronic HCV infection. In the near future, these novel therapies will have a profound impact on HCV prevalence and HCV-induced carcinogenesis. In this review, we discuss treatment options of HCV patients with both compensated and decompensated cirrhosis as well as HCV patients in pre- and post-transplantation settings with a focus on the currently available data on HCC development in these patient populations

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Different Prognostic Roles Of Tumor Suppressor Gene BAP1 In Cancer: A Systematic Review With Meta-Analysis

ABSTRACT

Biallelic inactivation of the tumor suppressor gene BRCA1-associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1- were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to BAP1- adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1-: n=697; BAP1+: n=2,750), with a median follow-up over 60 months, were meta-analyzed. Compared to BAP1+, BAP1- significantly increased all-cause mortality, cancer-specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high-tumor grading (p<0.0001), and that BAP1 mutated is more common in women than in men (p<0.0001). In conclusion, on the basis of our meta-analysis, we have demonstrated a peculiar role of BAP1 in influencing the prognosis in cancer. Thus, BAP1 could be considered as an important potential target for personalized medicine. This article is protected by copyright. All rights reserved.

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Epigenetic Regulation of SMARCB1 by miR-206, -381 and -671-5p is Evident in a Variety of SMARCB1 Immunonegative Soft Tissue Sarcomas, while miR-765 Appears Specific for Epithelioid Sarcoma. A miRNA Study of 223 Soft Tissue Sarcomas

Abstract

Complete/partial loss of SMARCB1 nuclear-immunopositivity is characteristic of a certain subset of soft tissue sarcomas. Our previous work showed that oncomiRs-206,-381, and 671-5p could silence the SMARCB1 mRNA and protein expression and that they display significant overexpression in epithelioid sarcomas (ESs). MiR-765 was overexpressed too, but functionally was inactive in the silencing. In the current work, using quantitative PCR, we conducted a miRNA study of 51 ESs, 20 rhabdoid tumors (RTs), 20 synovial sarcomas (SSs), 15 malignant peripheral nerve sheath tumors (MPNSTs), 11 myoepithelial carcinomas (MECs), and 10 extraskeletal myxoid chondrosarcomas (EMCSs) with complete/partial loss of SMARCB1 nuclear immunostain, in contrast to controls (SMARCB1-immunopositive) of 96 STSs, 13 melanomas and 10 sarcomatoid carcinomas. The SMARCB1 genetic status of ESs was determined by MLPA and FISH. A subset of ESs (5/51) showed biallelic deletion of SMARCB1 with no overexpression of any miRNA, suggesting these tumors could be the counterpart of pediatric RT, at least genetically. Another subset (5/51) was genetically either intact or monoallelic deleted with at least threefold overexpression of one of miR-206,-381,-671-5p, suggesting epigenetic regulation only. 39/51 ESs had biallelic deletion (>20% by FISH and/or by MLPA) but with overexpressed miR-206,-381, and 671-5p, suggesting intratumoral heterogeneity, i.e., both genetic and epigenetic regulation. At least threefold overexpression of one of miR-206,-381, and 671-5p was detected in all MPNSTs, EMCSs, SSs and 7 MCs. Except for ESs, four SSs and one MPNST, there was no event above threefold overexpression of miR-765 among all 195 tested tumors. Our results suggest a general role of miR-206,-381, and 671-5p in SMARCB1 gene silencing of ES, MC, EMCS, MPNST and SS. In the future, miR-765 could possibly be a diagnostic tool for ES because of its 97% specificity and 80% sensitivity. This article is protected by copyright. All rights reserved.

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Use, complications, and costs of stereotactic body radiotherapy for localized prostate cancer

BACKGROUND

Stereotactic body radiotherapy (SBRT) for localized prostate cancer has potential advantages over traditional radiotherapies. Herein, the authors compared national trends in use, complications, and costs of SBRT with those of traditional radiotherapies.

METHODS

The authors identified men who underwent SBRT, intensity-modulated radiotherapy (IMRT), brachytherapy, and proton beam therapy as primary treatment of prostate cancer between 2004 and 2011 from Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked data. Temporal trend of therapy use was assessed using the Cochran-Armitage test. Two-year outcomes were compared using the chi-square test. Median treatment costs were compared using the Kruskal-Wallis test.

RESULTS

A total of 542 men received SBRT, 9647 received brachytherapy, 23,408 received IMRT, and 800 men were treated with proton beam therapy. There was a significant increase in the use of SBRT and proton beam therapy (P<.001), whereas brachytherapy use decreased (P<.001). A higher percentage of patients treated with SBRT and brachytherapy had low-grade cancer (Gleason score ≤ 6 vs ≥ 7) compared with individuals treated with IMRT and proton beam therapy (54.0% and 64.2% vs 35.2% and 49.6%, respectively; P<.001). SBRT compared with brachytherapy and IMRT was associated with equivalent gastrointestinal toxicity but more erectile dysfunction at 2-year follow-up (P<.001). SBRT was associated with more urinary incontinence compared with IMRT and proton beam therapy but less compared with brachytherapy (P<.001, respectively). The median cost of SBRT was $27,145 compared with $17,183 for brachytherapy, $37,090 for IMRT, and $54,706 for proton beam therapy (P<.001).

CONCLUSIONS

The use of SBRT and proton beam therapy for localized prostate cancer has increased over time. Despite men of lower disease stage undergoing SBRT, SBRT was found to be associated with greater toxicity but lower health care costs compared with IMRT and proton beam therapy. Cancer 2016. © 2016 American Cancer Society.

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The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition

Summary

We have previously shown that the insulinotropic imidazoline compound RX871024 induces death of insulinoma MIN6 cells, an effect involving stimulation of c-Jun N-terminal kinase (JNK) and caspase 3. It has also been reported that AMP-activated protein kinase (AMPK) activates JNK and induces β-cell death. Here we show that RX871024, but not another insulinotropic imidazoline compound (BL11282), suppressed AMPK activity in MIN6 cells. The inhibitory effect of RX871024 on AMPK was supported by the observation that the imidazoline induced lipid droplet formation in the cytoplasm of MIN6 cells. This reflects stimulation of anabolic pathways and inhibition of catabolic pathways in the cell that happen under conditions when AMPK is inhibited. Activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) elevated basal and cytokine-induced death in primary β-cells and in insulinoma MIN6 cells. RX871024 aggravated AICAR-induced insulinoma MIN6 cell death regardless of the presence of pro-inflammatory cytokines. The specific cytotoxic effect of imidazoline compound RX871024 on insulinoma cell death but not primary β-cell death is independent of its action on AMPK and may suggest the possibility of using this type of compound in the treatment of insulinomas.

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Pharmacokinetics and excretion of 14 C-omacetaxine in patients with advanced solid tumors

Summary

Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of ¹⁴C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m²¹⁴C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4′-desmethylhomoharringtonine (4′-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m² omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4′ DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other ¹⁴C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of ¹⁴C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other ¹⁴C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.

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The Pattern of Use of Hypofractionated Radiation Therapy for Early Stage Breast Cancer in New South Wales, Australia, 2008-2012

Publication date: Available online 24 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Geoff P. Delaney, Senthilkumar Gandhidasan, Richard Walton, Frances Terlich, Deborah Baker, David Currow
PurposeIncreasing Phase III evidence has been published about the safety and efficacy of hypofractionated radiotherapy, in comparison with standard fractionation, in early-stage, node-negative breast cancer. However, uptake of hypofractionation has not been universal. The aim of this study was to investigate the hypofractionation regimen variations in practice across public radiation oncology facilities in NSW.Methods and MaterialsPatients with early breast cancer registered in the NSW Clinical Cancer Registry that received radiotherapy treatment for early stage breast cancer in a publicly-funded radiotherapy department between 2008 and 2012 were identified. Data extracted and analysed included dose and fractionation type, patient age at first fraction, address (for geo-coding), year of diagnosis, year of treatment, laterality and, department of treatment. A logistic regression model was used to identify factors associated with fractionation typeResultsOf the 5880 patients fulfilling the study criteria, 3209 patients (55%) had standard fractionation and 2671 patients (45%) received hypofractionation Overall, the use of hypofractionation increased from 37% in 2008 to 48% in 2012 (range = 7-94% across departments). Treatment facility and the radiation oncologist prescribing the treatment were the strongest independent predictors of hypofractionation. Weaker associations were also found for age, tumor site laterality, year of treatment, and distance to facility.ConclusionsHypofractionated regimens of whole-breast radiation therapy have been variably administered in the adjuvant setting in NSW despite the publication of long-term trial results and consensus guidelines. Some factors that predict the use of hypofractionation are not based on guideline recommendations, including lower rates of left-sided treatment and increasing distance from a treatment facility.

Teaser

A retrospective audit of early stage breast cancer patients treated with radiotherapy in New South Wales (NSW) departments 2008-2012 was performed using NSW Clinical Cancer Registry data. The use of hypofractionation is rising but still lower, at 45%, than would be expected based on treatment guidelines. Factors that correlated significantly with hypofractionation use were age, laterality, year, distance of patient residence from the department, treating facility and radiation oncologist.


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A Phase I Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer following modified FOLFIRINOX

Publication date: Available online 24 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Walid L. Shaib, Natalyn Hawk, Richard J. Cassidy, Zhengjia Chen, Chao Zhang, Edith Brutcher, David Kooby, Shishir K. Maithel, Juan M. Sarmiento, Jerome Landry, Bassel F. El-Rayes
In borderline resectable pancreatic cancer management, high rates of positive posterior margin (PM) are reported. Stereotactic body radiation therapy (SBRT) allows higher radiation doses. SBRT escalation dose was evaluated in a single institution, 3+3 phase I clinical trial delivered after 2 cycles of modified FOLFIRINOX. We planned 4 dose levels (DL) delivered in 3 fractions. DL-4 (45 Gy included 9 Gy to PM) was safe. Further dose escalations are needed.



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Disruption of collagen fibril alignment attenuates cancer

Abnormal architectures of collagen fibers in the extracellular matrix (ECM) are hallmarks of many invasive diseases, including cancer. Targeting specific stages of collagen assembly in vivo presents a great challenge due to the involvement of various crosslinking enzymes in the multi-step, hierarchical process of ECM build-up. Using advanced microscopic tools, we monitored stages of fibrillary collagen assembly in a native fibroblast-derived 3D matrix system, and identified anti-lysyl oxidase like 2 (LOXL2) antibodies that alter the natural alignment and width of endogenic fibrillary collagens without affecting ECM composition. The disrupted collagen morphologies interfered with the adhesion and invasion properties of human breast cancer cells. Treatment of mice bearing breast cancer xenografts with the inhibitory antibodies resulted in disruption of the tumorigenic collagen super-structure and in reduction of primary tumor growth. Our approach could serve as a general methodology to identify novel therapeutics targeting fibrillary protein organization to treat ECM-associated pathologies.

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miR-211-TCF12-FAM213A activation in OSCC

miR-211 expression in human oral squamous cell carcinoma (OSCC) has been inmplicated in poor patient survival. To investigate the oncogenic roles of miR-211, we generated K14-EGFP-miR-211 transgenic mice tagged with green fluorescence protein. Induction of oral carcinogenesis in transgenic mice using 4-nitroquinoline 1-oxide (4NQO) resulted in more extensive and severe tongue tumorigenesis compared with control animals. We found that 4NQO and arecoline upregulated miR-211 expression in OSCC cells. In silico and experimental evidence further revealed that miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically downregulated in tumor tissues. We used GeneChip analysis and bioinformatic algorithms to identify transcriptional targets of TCF12 and confirmed through reporter and ChIP assays that FAM213A, a peroxiredoxin-like anti-oxidative protein, was repressed transcriptionally by TCF12. FAM213A silencing in OSCC cells diminished oncogenic activity, reduced the ALDH1-positive cell population and increased reactive oxygen species. TCF12 and FAM213A expression was correlated inversely in head and neck carcinoma samples according to The Cancer Genome Atlas. OSCC patients bearing tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment downregulated TCF12 and upregulated FAM213A by modulating miR-211 both in vitro and in vivo. Overall, our findings develop a mouse model that recapitulates the molecular and histopathological alterations of human OSCC pathogenesis and highlight a new microRNA-mediated oncogenic mechanism.

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A2BR promotes cancer metastasis

Adenosine plays an important role in inflammation and tumor development, progression and responses to therapy. We show that an adenosine 2B receptor inhibitor (A2BRi) decreases both experimental and spontaneous metastasis and combines with chemotherapy or immune checkpoint inhibitors in mouse models of melanoma and triple-negative breast cancer (TNBC) metastasis. Decreased metastasis upon A2BR inhibition is independent of host A2BR and lymphocytes and myeloid cells. Knockdown of A2BR on mouse and human cancer cells reduces their metastasis in vivo and decreases their viability and colony forming ability, while transiently delaying cell cycle arrest in-vitro. The pro-metastatic activity of adenosine is partly tumor A2BR-dependent and independent of host A2BR expression. In humans, TNBC cell lines express higher A2BR than luminal and Her2+ breast cancer cell lines and high expression of A2BR is associated with worse prognosis in TNBC. Collectively, high A2BR on mouse and human tumors promotes cancer metastasis and is an ideal candidate for therapeutic intervention.

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EMT-induced TF and pro-coagulant properties of CTCs

Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTC with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related pro-coagulant properties in the blood. TF blockade by antibody or shRNA diminished the pro-coagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis which triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTC.

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HPV-induced tumors control by CD8+ cells and MDSC depletion

Active anti-cancer immunotherapeutic approaches have been shown to induce cellular or humoral immune responses in patients, but thus far, the observed outcomes did not ensure their recommendation for clinical use. The induction of tumor-specific CD8+ T cells, although required for the clearance of most solid tumors, showed to be insufficient for the development of a successful immunotherapeutic approach. The suppressive immune environment triggered by tumors, including the expansion of myeloid-derived suppressor cells (MDSCs), is detrimental to the development of antitumor immune responses and precludes the generation of more promising clinical outcomes. In the present work, we characterized the CD8+ T cell population specifically involved in the control of tumor growth and the role of MDSCs after administration of an antitumor therapeutic DNA vaccine targeting human papillomavirus type 16 (HPV-16)-associated tumors. In mice grafted with tumor cells expressing the HPV-16 oncoproteins, led to the activation of cytotoxic high-avidity CD8+ T cells with an effector memory phenotype. In addition, MDSC antibody depletion further enhanced the immunotherapeutic effects of the vaccine, resulting in the complete eradication of tumor cells. Collectively, the present results indicate that the simultaneous control of MDSCs and activation of high-avidity tumor-specific effector memory CD8+ T cells are key features for tumor protection by immunotherapeutic approaches and deserve further testing under clinical conditions.

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The MAPK Pathway Facilitates Resistance to Dasatinib

Advanced stages of papillary and anaplastic thyroid cancer represent a highly aggressive subset, in which there are currently few effective therapies. We and others have recently demonstrated that c-Src is a key mediator of growth, invasion, and metastasis, and therefore represents a promising therapeutic target in thyroid cancer. However clinically, Src inhibitor efficacy has been limited, and therefore further insights are needed to define resistance mechanisms and determine rational combination therapies. We have generated four thyroid cancer cell lines with a greater than 30-fold increase in acquired resistance to the Src inhibitor, dasatinib. Upon acquisition of dasatinib-resistance, the two RAS-mutant cell lines acquired the c-Src gatekeeper mutation (T341M), whereas the two BRAF-mutant cell lines did not. Accordingly, Src signaling was refractory to dasatinib treatment in the RAS-mutant dasatinib-resistant cell lines. Interestingly, activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib. We further demonstrate that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single agent inhibition.

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