The prognostic impact of programmed cell death ligand 1 and human leukocyte antigen class I in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive tumor-microenvironment (TME) that supports the growth of tumors and mediates tumors enabling evasion of the immune system. Expression of programmed cell death ligand 1 (PD-L1) and loss of human leukocyte antigen (HLA) class I on tumor cells are methods by which tumors escape immunosurveillance. We examined immune cell infiltration, the expression of PD-L1 and HLA class I by PDA cells, and the correlation between these immunological factors and clinical prognosis. PDA samples from 36 patients were analyzed for HLA class I, HLA-DR, PD-L1, PD-1, CD4, CD8, CD56, CD68, and FoxP3 expression by immunohistochemistry. The correlations between the expression of HLA class I, HLA-DR, PD-L1 or PD-1 and the pattern of tumor infiltrating immune cells or the patients' prognosis were assessed. PD-L1 expression correlated with tumor infiltration by CD68⁺ and FoxP3⁺ cells. Low HLA class I expression was an only risk factor for poor survival. PD-L1 negative and HLA class I high-expressing PDA was significantly associated with higher numbers of infiltrating CD8⁺ T cells in the TME, and a better prognosis. Evaluation of both PD-L1 and HLA class I expression by PDA may be a good predictor of prognosis for patients. HLA class I expression by tumor cells should be evaluated when selecting PDA patients who may be eligible for treatment with PD-1/PD-L1 immune checkpoint blockade therapies.

The expression of PD-L1 did not alter the patients' prognosis if their tumors were HLA class I low, but it did for those with HLA class I high tumors. These findings suggest that the evaluation of PD-L1 and HLA class I expression is useful to predict the patients' prognosis and HLA class I should be a new biomarker to select patients who may benefit from anti-PD-1/PD-L1-based immunotherapy.

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The prognostic impact of programmed cell death ligand 1 and human leukocyte antigen class I in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive tumor-microenvironment (TME) that supports the growth of tumors and mediates tumors enabling evasion of the immune system. Expression of programmed cell death ligand 1 (PD-L1) and loss of human leukocyte antigen (HLA) class I on tumor cells are methods by which tumors escape immunosurveillance. We examined immune cell infiltration, the expression of PD-L1 and HLA class I by PDA cells, and the correlation between these immunological factors and clinical prognosis. PDA samples from 36 patients were analyzed for HLA class I, HLA-DR, PD-L1, PD-1, CD4, CD8, CD56, CD68, and FoxP3 expression by immunohistochemistry. The correlations between the expression of HLA class I, HLA-DR, PD-L1 or PD-1 and the pattern of tumor infiltrating immune cells or the patients' prognosis were assessed. PD-L1 expression correlated with tumor infiltration by CD68⁺ and FoxP3⁺ cells. Low HLA class I expression was an only risk factor for poor survival. PD-L1 negative and HLA class I high-expressing PDA was significantly associated with higher numbers of infiltrating CD8⁺ T cells in the TME, and a better prognosis. Evaluation of both PD-L1 and HLA class I expression by PDA may be a good predictor of prognosis for patients. HLA class I expression by tumor cells should be evaluated when selecting PDA patients who may be eligible for treatment with PD-1/PD-L1 immune checkpoint blockade therapies.

The expression of PD-L1 did not alter the patients' prognosis if their tumors were HLA class I low, but it did for those with HLA class I high tumors. These findings suggest that the evaluation of PD-L1 and HLA class I expression is useful to predict the patients' prognosis and HLA class I should be a new biomarker to select patients who may benefit from anti-PD-1/PD-L1-based immunotherapy.

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Title page / Editorial Board

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48





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Table of contents

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48





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Title page / Editorial Board

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48





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Table of contents

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48





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Obstacles, Opportunities and Priorities for Advancing Metastatic Breast Cancer Research

In January 2016, the Metastatic Breast Cancer Alliance (the Alliance) convened a think tank of stakeholders from academia, government, industry, and patient advocacy to discuss gaps and opportunities in clinical and translational research in metastatic breast cancer. Priorities that emerged from the meeting included the following: the need for innovative preclinical model systems to study metastatic disease; increased sharing of resources and data; collaboration across cancer care teams and scientists; biorepositories for studies to identify biomarkers for treatment response; creation of patient registries to increase access to clinical trials and tissue procurement; and redesign of clinical trials in metastatic breast cancer. Cancer Res; 1–5. ©2017 AACR.

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Obstacles, Opportunities and Priorities for Advancing Metastatic Breast Cancer Research

In January 2016, the Metastatic Breast Cancer Alliance (the Alliance) convened a think tank of stakeholders from academia, government, industry, and patient advocacy to discuss gaps and opportunities in clinical and translational research in metastatic breast cancer. Priorities that emerged from the meeting included the following: the need for innovative preclinical model systems to study metastatic disease; increased sharing of resources and data; collaboration across cancer care teams and scientists; biorepositories for studies to identify biomarkers for treatment response; creation of patient registries to increase access to clinical trials and tissue procurement; and redesign of clinical trials in metastatic breast cancer. Cancer Res; 1–5. ©2017 AACR.

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Editorial Board

Publication date: June 2017
Source:Cancer/Radiothérapie, Volume 21, Issue 4





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Issue Contents

Publication date: June 2017
Source:Cancer/Radiothérapie, Volume 21, Issue 4





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Editorial Board

Publication date: June 2017
Source:Cancer/Radiothérapie, Volume 21, Issue 4





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Issue Contents

Publication date: June 2017
Source:Cancer/Radiothérapie, Volume 21, Issue 4





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Bilateral ocular ischemia-induced blindness as a presenting manifestation of Takayasu arteritis: a case report

Takayasu arteritis is a granulomatous panarteritis that predominantly affects the aorta and its major branches. The initial manifestations of this large-vessel vasculitis are usually nonspecific; however, as t...

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Survival improvement in hormone-responsive young breast cancer patients with endocrine therapy

Abstract

Purpose

We investigated the oncologic outcomes by intrinsic subtype and age in young breast cancer patients and whether survival differences were related to treatment changes over time.

Methods

A retrospective analysis was performed on 9633 invasive breast cancer patients treated at Asan Medical Center from January 1989 to December 2008. We also enrolled a matched cohort adjusting for tumor size, lymph node metastasis, subtypes, and tumor grade. Patients aged <35 years were included in the younger group (n = 602) and those aged ≥35 years were included in the older group (n = 3009).

Results

The younger patients showed a significantly higher T stage, a more frequent axillary node presentation, higher histologic grade, and higher incidence of triple-negative subtype tumors than older patients and also received more chemotherapy and were less likely to undergo hormone therapy. The younger patients with hormone receptor (HR)-positive tumors showed significantly poorer disease-free survival (DFS), loco-regional recurrence-free survival, distant metastasis-free survival, and breast cancer-specific survival outcomes than older patients. Younger patients with HR-positive and human epidermal growth factor receptor 2 (HER2)-negative tumor subtypes had a significantly improved DFS over time (p = 0.032). Within the HR-positive/Her2-negative subtype, more women received gonadotropin-releasing hormone agonist and tamoxifen treatment from 2003 to 2008 compared with 1989 to 2002 (p = 0.001 and p = 0.075, respectively).

Conclusions

HR-positive young breast cancer patients have a poorer survival compared with older patients, even with more frequent chemotherapy, but more recent use of tamoxifen and ovarian suppression might improve this outcome in these patients.

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Fludarabine inhibits STAT1-mediated up-regulation of caspase-3 expression in dexamethasone-induced osteoblasts apoptosis and slows the progression of steroid-induced avascular necrosis of the femoral head in rats

Abstract

Steroid-induced avascular necrosis of the femoral head (SANFH) is a major limitation of long-term or excessive clinical administration of glucocorticoids. Fludarabine, which is a compound used to treat various hematological malignancies, such as chronic lymphocytic leukemia, acts by down-regulating signal transducer and activator of transcription 1 (STAT1) by inhibiting STAT1 phosphorylation in both normal and cancer cells. This study assessed the effects of fludarabine in vitro (primary murine osteoblasts) and in vivo (rat SANFH model). In vitro, pretreatment with fludarabine significantly inhibited Dexamethasone (Dex)-induced apoptosis in osteoblasts, which was examined by TUNEL staining. Treatment with Dex caused a remarkable decrease in the expression of Bcl-2; an increase in cytochrome c release; activation of BAX, caspase-9, and caspase-3; and an obvious enhancement in STAT1 phosphorylation. However, treatment resulted in the up-regulation of caspase-3 expression. Enhanced P-STAT1 activity and up-regulation of caspase-3 expression were also observed in osteoblasts. In vivo, the subchondral trabeculae in fludarabine-treated rats exhibited less bone loss and a lower ratio of empty lacunae. Taken together, our results suggest that STAT1-mediated up-regulation of caspase-3 is involved in osteoblast apoptosis induced by Dex and indicates that fludarabine may serve as a potential agent for the treatment of SANFH.

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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

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Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma

Publication date: Available online 9 June 2017
Source:Cell Stem Cell
Author(s): Tobias L. Haas, Maria Rita Sciuto, Lidia Brunetto, Cecilia Valvo, Michele Signore, Micol E. Fiori, Simona di Martino, Stefano Giannetti, Liliana Morgante, Alessandra Boe, Michele Patrizii, Uwe Warnken, Martina Schnölzer, Andrea Ciolfi, Chiara Di Stefano, Mauro Biffoni, Lucia Ricci-Vitiani, Roberto Pallini, Ruggero De Maria
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.

Graphical abstract

Teaser

Haas et al. identify integrin α7 as a functional marker of glioblastoma stem cells by screening a monoclonal antibody library generated against primary glioblastoma (GBM) cells. Functional experiments in culture and in vivo show that the targeting of integrin α7 has potential as a therapeutic avenue for treating this aggressive disease.


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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

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A novel systemic immune-inflammation index predicts survival and quality of life of patients after curative resection for esophageal squamous cell carcinoma

Abstract

Purpose

A novel systemic immune-inflammation index (SII) based on platelet (P), neutrophil (N), and lymphocyte (L) counts has been reported to be associated with clinical outcomes in several solid tumors. We aimed to investigate its prognostic value in esophageal squamous cell carcinoma (ESCC) and the potential relationship with quality of life (QOL).

Methods

A total of 280 ESCC patients who underwent esophagectomy were enrolled. SII (SII = P × N/L) was calculated on the basis of data obtained within 1 week before surgery. An optimal cut-off value stratified patients into high (≥560) and low (<560) preoperative SII groups. The widely used EORTC QLQ-C30 and QLQ-OES18 were utilized to assess QOL at cancer diagnosis and 36 months after surgery. Generalized estimating equations (GEEs) were used to evaluate the association of SII with QOL. Kaplan–Meier method and Cox proportional regression were used to analyze the prognostic value of SII.

Results

Kaplan–Meier analyses revealed that higher SII correlated significantly with poorer overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p < 0.001) in patients with ESCC. Multivariate analysis identified SII as an independent prognostic factor for OS (p < 0.001; HR 2.578; 95% CI 1.625–4.088) and DFS (p < 0.001; HR 2.699; 95% CI 1.726–4.223). In addition, patients with high SII exhibited notably deteriorating QOL (p < 0.05).

Conclusions

The preoperative SII is a promising biomarker for predicting survival and QOL of patients with ESCC. It may help to identify the high-risk patients for treatment strategy decisions.

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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-γ and multiple toll-like receptor agonists

Abstract

Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFNγ and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFNγ, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFNγ, R848, and poly I:C had the ability to activate IFNγ production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFNγ and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.

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Social media for breast cancer survivors: a literature review

Abstract

Purpose

Social media may offer support to individuals who are navigating the complex and challenging experience of cancer. A growing body of literature has been published over the last decade exploring the ways cancer survivors utilize social media. This study aims to provide a systematic synthesis of the current literature in order to inform cancer health communication practice and cancer survivorship research.

Methods

Using PRISMA guidelines, four electronic databases were searched to retrieve publications on breast cancer and social media published between 2005 and 2015. The final sample included 98 publications (13 commentaries and reviews, 47 descriptive studies, and 38 intervention studies). Intervention studies were assessed for key features and outcome measures. Studies utilizing content analysis were further evaluated qualitatively.

Results

Online support groups were the most commonly studied platform, followed by interactive message boards and web forums. Limited research focuses on non-Caucasian populations. Psychosocial well-being was the most commonly measured outcome of interest. While social media engagement was assessed, few standardized measures were identified. Content analyses of social media interactions were prevalent, though few articles linked content to health outcomes.

Conclusions

The current literature highlights the impact and potential utility of social media for breast cancer survivors. Future studies should consider connecting social media engagement and content to psychosocial, behavioral, and physical health outcomes.

Implications for Cancer Survivors

Online groups and communities may improve the well-being of breast cancer survivors by providing opportunities to engage with wider social networks, connect with others navigating similar cancer experiences, and obtain cancer-related information. Researchers should consider the potential role of social media in addressing the unmet needs of breast cancer survivors, and particularly the implications for clinical and public health practice.

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Social media for breast cancer survivors: a literature review

Abstract

Purpose

Social media may offer support to individuals who are navigating the complex and challenging experience of cancer. A growing body of literature has been published over the last decade exploring the ways cancer survivors utilize social media. This study aims to provide a systematic synthesis of the current literature in order to inform cancer health communication practice and cancer survivorship research.

Methods

Using PRISMA guidelines, four electronic databases were searched to retrieve publications on breast cancer and social media published between 2005 and 2015. The final sample included 98 publications (13 commentaries and reviews, 47 descriptive studies, and 38 intervention studies). Intervention studies were assessed for key features and outcome measures. Studies utilizing content analysis were further evaluated qualitatively.

Results

Online support groups were the most commonly studied platform, followed by interactive message boards and web forums. Limited research focuses on non-Caucasian populations. Psychosocial well-being was the most commonly measured outcome of interest. While social media engagement was assessed, few standardized measures were identified. Content analyses of social media interactions were prevalent, though few articles linked content to health outcomes.

Conclusions

The current literature highlights the impact and potential utility of social media for breast cancer survivors. Future studies should consider connecting social media engagement and content to psychosocial, behavioral, and physical health outcomes.

Implications for Cancer Survivors

Online groups and communities may improve the well-being of breast cancer survivors by providing opportunities to engage with wider social networks, connect with others navigating similar cancer experiences, and obtain cancer-related information. Researchers should consider the potential role of social media in addressing the unmet needs of breast cancer survivors, and particularly the implications for clinical and public health practice.

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TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies

Abstract

Purpose

This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

Methods

Sixty-seven patients received TAK-228 6–40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m² (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1.

Results

TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months.

Conclusion

TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors.

Clinicaltrials.gov identifier

NCT01351350.

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Postoperative pulmonary complications following non-cardiothoracic surgery

1H022A073A03

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TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies

Abstract

Purpose

This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

Methods

Sixty-seven patients received TAK-228 6–40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m² (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1.

Results

TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months.

Conclusion

TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors.

Clinicaltrials.gov identifier

NCT01351350.

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TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies

Abstract

Purpose

This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

Methods

Sixty-seven patients received TAK-228 6–40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m² (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1.

Results

TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months.

Conclusion

TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors.

Clinicaltrials.gov identifier

NCT01351350.

http://ift.tt/2sozOp3

Salvage endoscopic nasopharyngectomy for local recurrent or residual nasopharyngeal carcinoma: a 10-year experience

Abstract

Background

Our aim was to review the outcomes of endoscopic nasopharyngectomy performed on a large series of patients with residual or recurrent nasopharyngeal carcinomas and to identify the prognostic factors.

Methods

Ninety-one patients with residual (10) and recurrent (81) nasopharyngeal carcinomas who underwent endoscopic nasopharyngectomy were enrolled in our study. Clinical information including gender, age, medical history, symptoms, radiographic findings, tumor stage, treatment, recurrence time, postoperative pathological examination, complications, and outcomes at last follow-up visit was collected. The survival curves and multivariate survival analysis were analyzed using the Kaplan–Meier and Cox proportional hazards model.

Results

Our study included 71 men and 20 women with a median age of 51 years. The lesions were staged as follows: rT1, 30; rT2, 13; rT3, 29; and rT4, 19. No serious operative or postoperative complication was observed. The median follow-up period was 23 months (range, 4–109 months). Tumor necrosis was identified in 40 of 91 patients. At the last follow-up, 42 patients were free of disease, 10 were alive with disease, and 39 had died. At 2- and 5-year follow-up, the overall survival rates were 64.8% and 38.3%, respectively; the disease-free survival rates were 57.5% and 30.2%, respectively, for the two periods. Multivariate analysis showed that T classification (P = 0.02) and tumor necrosis (P = 0.024) were independent risk factors.

Conclusions

Endoscopic nasopharyngectomy is a feasible and effective surgical treatment for recurrent and residual nasopharyngeal carcinomas.

http://ift.tt/2soLOqD

Salvage endoscopic nasopharyngectomy for local recurrent or residual nasopharyngeal carcinoma: a 10-year experience

Abstract

Background

Our aim was to review the outcomes of endoscopic nasopharyngectomy performed on a large series of patients with residual or recurrent nasopharyngeal carcinomas and to identify the prognostic factors.

Methods

Ninety-one patients with residual (10) and recurrent (81) nasopharyngeal carcinomas who underwent endoscopic nasopharyngectomy were enrolled in our study. Clinical information including gender, age, medical history, symptoms, radiographic findings, tumor stage, treatment, recurrence time, postoperative pathological examination, complications, and outcomes at last follow-up visit was collected. The survival curves and multivariate survival analysis were analyzed using the Kaplan–Meier and Cox proportional hazards model.

Results

Our study included 71 men and 20 women with a median age of 51 years. The lesions were staged as follows: rT1, 30; rT2, 13; rT3, 29; and rT4, 19. No serious operative or postoperative complication was observed. The median follow-up period was 23 months (range, 4–109 months). Tumor necrosis was identified in 40 of 91 patients. At the last follow-up, 42 patients were free of disease, 10 were alive with disease, and 39 had died. At 2- and 5-year follow-up, the overall survival rates were 64.8% and 38.3%, respectively; the disease-free survival rates were 57.5% and 30.2%, respectively, for the two periods. Multivariate analysis showed that T classification (P = 0.02) and tumor necrosis (P = 0.024) were independent risk factors.

Conclusions

Endoscopic nasopharyngectomy is a feasible and effective surgical treatment for recurrent and residual nasopharyngeal carcinomas.

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Granulin-epithelin precursor interacts with 78-kDa glucose-regulated protein in hepatocellular carcinoma

Abstract

Background

Granulin-epithelin precursor (GEP) is a secretory growth factor, which has been demonstrated to control cancer growth, invasion, drug resistance and immune escape. Our previous studies and others also demonstrated its potential in targeted therapy. Comprehensive characterization of GEP partner on cancer cells are warranted. We have previously shown that GEP interacted with heparan sulfate on the surface of liver cancer cells and the interaction is crucial for GEP-mediated signaling transduction. This study aims to characterize GEP protein partner at the cell membrane with the co-immunoprecipitation and mass spectrometry approach.

Methods

The membrane fraction from liver cancer model Hep3B was used for capturing binding partner with the specific monoclonal antibody against GEP. The precipitated proteins were analyzed by mass spectrometry. After identifying the GEP binding partner, this specific interaction was validated in additional liver cancer cell line HepG2 by co-immunoprecipitation using GRP78 and GEP antibodies, respectively, as the bait. GRP78 transcript levels in hepatocellular carcinoma (HCC) clinical samples (n = 77 pairs) were examined by real-time quantitative RT-PCR. GEP and GRP78 protein expressions were investigated by immunohistochemistry on paraffin sections.

Results

We identified the GEP-binding protein as 78-kDa glucose-regulated protein (GRP78, also named heat shock 70-kDa protein 5, HSPA5). This interaction was validated in independent HCC cell lines. Increased GRP78 mRNA levels were demonstrated in liver cancer tissues compared with the paralleled liver tissues (t-test, P = 0.002). GRP78 and GEP transcript levels were significantly correlated (Spearman's correlation, P = 0.001), and the proteins were also detectable in the cytoplasm of liver cancer cells by immunohistochemical staining.

Conclusions

GRP78 and GEP are interacting protein partners in liver cancer cells and may play a role in GEP-mediated cancer progression in HCC.

http://ift.tt/2t5U2k6

Granulin-epithelin precursor interacts with 78-kDa glucose-regulated protein in hepatocellular carcinoma

Abstract

Background

Granulin-epithelin precursor (GEP) is a secretory growth factor, which has been demonstrated to control cancer growth, invasion, drug resistance and immune escape. Our previous studies and others also demonstrated its potential in targeted therapy. Comprehensive characterization of GEP partner on cancer cells are warranted. We have previously shown that GEP interacted with heparan sulfate on the surface of liver cancer cells and the interaction is crucial for GEP-mediated signaling transduction. This study aims to characterize GEP protein partner at the cell membrane with the co-immunoprecipitation and mass spectrometry approach.

Methods

The membrane fraction from liver cancer model Hep3B was used for capturing binding partner with the specific monoclonal antibody against GEP. The precipitated proteins were analyzed by mass spectrometry. After identifying the GEP binding partner, this specific interaction was validated in additional liver cancer cell line HepG2 by co-immunoprecipitation using GRP78 and GEP antibodies, respectively, as the bait. GRP78 transcript levels in hepatocellular carcinoma (HCC) clinical samples (n = 77 pairs) were examined by real-time quantitative RT-PCR. GEP and GRP78 protein expressions were investigated by immunohistochemistry on paraffin sections.

Results

We identified the GEP-binding protein as 78-kDa glucose-regulated protein (GRP78, also named heat shock 70-kDa protein 5, HSPA5). This interaction was validated in independent HCC cell lines. Increased GRP78 mRNA levels were demonstrated in liver cancer tissues compared with the paralleled liver tissues (t-test, P = 0.002). GRP78 and GEP transcript levels were significantly correlated (Spearman's correlation, P = 0.001), and the proteins were also detectable in the cytoplasm of liver cancer cells by immunohistochemical staining.

Conclusions

GRP78 and GEP are interacting protein partners in liver cancer cells and may play a role in GEP-mediated cancer progression in HCC.

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[Internal quality control on HER2 status determination in breast cancers: Experience of a cancer center].

Related Articles

[Internal quality control on HER2 status determination in breast cancers: Experience of a cancer center].

Bull Cancer. 2017 Jun 05;:

Authors: Ngo C, Laé M, Ratour J, Hamel F, Taris C, Caly M, Le Cunff A, Reyal F, Kirova Y, Pierga JY, Vincent-Salomon A

Abstract
INTRODUCTION: The implementation of an internal quality control is mandatory to guarantee the accuracy of HER2 status in invasive breast cancers.
OBJECTIVES: To evaluate the impact of our quality control assurance on HER2 status results in invasive breast carcinomas from 2008 to 2014.
METHODS: HER2 status was determined by immunohistochemistry as the first-line indication, completed by fluorescence in situ hybridization (FISH) for scores 2+ by immunohistochemistry. Internal quality control of HER2 status relied on the standardization of pre-analytical phases, the use of external controls with a known number of HER2 gene copies determined by FISH and continued monitoring of concordance between immunohistochemistry and FISH.
RESULTS: The proportion of HER2-positive cases corresponding to scores 3+ by immunohistochemistry and 2+ amplified by FISH varied from 10.6% to 13.8% (median of 11.3%). The proportion of scores 2+ amplified by FISH varied from 13.3% to 32.7% during period of study. The rate of concordance between FISH and immunohistochemistry for score 0/1+ and 3+ cases were≥97%. Eight among 12 discordant cases were false positive resulting from errors in interpretation of immunohistochemistry (score 2+ instead of 3+).
DISCUSSION: Calibration of immunohistochemistry on FISH for HER2 status contributes to limit variability of immunohistochemistry results due to technical issues or interpretation. The implementation of an external control of score 3+ on each slide enables accurate interpretation of score 2+ and 3+ by immunohistochemistry.

PMID: 28595742 [PubMed - as supplied by publisher]

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Clinical Outcomes of Large Brain Metastases Treated with Neurosurgical Resection and Intraoperative Cesium-131 Brachytherapy: Results of a Prospective Trial

Publication date: Available online 10 June 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Gabriella A. Wernicke, Cole B. Hirschfeld, Andrew W. Smith, Shoshana Taube, Menachem Z. Yondorf, Bhupesh Parashar, Lucy Nedialkova, Fridon Kulidzhanov, Samuel Trichter, Albert Sabbas, Rohan Ramakrishna, Susan Pannullo, Theodore H. Schwartz
BackgroundStudies on adjuvant stereotactic radiosurgery (SRS) to the cavity of resected brain metastases suggest that larger tumors (>2.0 cm) have higher rates of recurrence and radionecrosis (RN). This study assesses the impact of permanent low-dose ¹³¹Cs brachytherapy on local control and RN in patients treated for large brain metastases.MethodsAfter IRB approval, 42 patients with a total of 46 metastases >2.0 cm in preoperative diameter were accrued onto a prospective trial between 2010 and 2015. Patients underwent surgical resection with intra-operative placement of stranded ¹³¹Cs seeds as permanent volume implants in the resection cavity. The primary endpoint was local freedom from progression (FFP). Secondary endpoints included regional and distant FFP, overall survival (OS), and RN rate. Failures between 5 mm and 20 mm from the cavity, as well as dural-based failures, were considered regional. Separate analysis was performed for metastases > 3.0 cm.ResultsOf the 46 metastases, 18 were > 3.0 cm in diameter. The median follow-up period was 11.9 months (range, 0.6 – 51.9 months). Metastases had a median preoperative diameter of 3.0 cm (range, 2.0 – 6.8 cm). Local FFP was 100% for all tumor sizes. Regional recurrences were found in 3/46 (7%) lesions, yielding a 1-year region FFP of 89% (for tumors > 3.0 cm this was 80% (95% CI 54%, 100%). Distant recurrences were found in 19/46 (41%) patients yielding a 1-year distant FFP of 52%. The median OS was 15.1 months with a 1-year OS of 58%. Lesion size was not significantly associated with any endpoint in univariate or multivariate analysis. Radioresistant histology had worse survival (p=0.036). There were no cases of RN.ConclusionIntraoperative ¹³¹Cs brachytherapy is a promising and effective therapy for large brain metastases requiring neurosurgical intervention, which may offer improved local control and lower rates of RN compared with SRS to the resection cavity.

Teaser

Treating brain metastases ≥2 cm with radiation remains a challenge. Results from traditional techniques such as stereotactic radiosurgery are worse with larger lesions compared to smaller lesions. Here we present an alternative technique to treat large brain metastases using neurosurgical resection and intraoperative brachytherapy using a novel radioisotope, Cesium-131. Our study presents evidence that Cesium-131 results in high rates of local control, minimizes the risk of radionecrosis, and represents a safe and effective adjuvant therapy.


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Precision Oncology and Genomically Guided Radiation Therapy, A Report From the ASTRO/AAPM/NCI Precision Medicine Conference

Publication date: Available online 9 June 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): William A. Hall, Carmen Bergom, Reid F. Thompson, Andrew M. Baschnagel, Srinivasan Vijayakumar, Henning Willers, Allen Li, Christopher J. Schultz, George D. Wilson, Catharine M.L. West, Jacek Capala, C. Norman Coleman, Javier F. Torres-Roca, Joanne Weidhaas, Felix Y. Feng
BackgroundPrecision medicine and oncology is rapidly becoming the central principle of cancer management. Radiation oncologists provide a precise and highly personalized oncologic modality. Our speciality will need to fully embrace personalized and genomically guided treatment recommendations or miss an opportunity to improve the outcomes of our patients.MethodsThe American Society for Radiation Oncology (ASTRO), American Association of Physicists in Medicine (AAPM), and National Cancer Institute (NCI), co-sponsored a precision medicine in radiation oncology meeting. At this conference numerous scientist, clinicians, and physicists conveined in June of 2016 at the National Instititues of Health (NIH) to discuss challenges and future directions toward personalized radiation therapy. Various breakout sessions were held to discuss particular components and approaches to the implementation of personalized radiation oncology. This manuscript serves to summarize the genomically guided radiation therapy breakout session.ResultsA summary of exsisting genomic data enabling personalized radiation therapy, ongoing clinical trials, current challenges, and future directions was collected. The group attempted to provide both a current overview of data that radiation oncologists could use to personalize therapy, along with data that is anticipated in the coming years. It seems apparent from the provided review that a considerable opportunity exists to truly bring genomically guided radiation therapy into clinical reality.ConclusionsGenomically guided radiation therapy is a necessity that must be embraced in the coming years. Incorporating this data into treatment recommendations will provide radiation oncologists with a substantial opportunity to improve outcomes for numerous cancer patients. More research focused on this topic is needed to bring genomic signatures into routine standard of care.

Teaser

Radiation therapy is an incredibly precise and increasingly adaptable therapeutic modality. There is a significant amount of data showing that genomic metrics can significantly influence the outcomes for numerous malignancies treated with radiation therapy. Despite this, current standards of care do little to adapt radiation therapy based on genomic or tumor specific biological factors. This manuscript summarizes the current state of integrating genomic and biologic data into management strategies with radiation therapy.


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The results of Low dose Total Skin Electron Beam Radiotherapy (TSEB), in patients with mycosis fungoides from the UK cutaneous lymphoma group

Publication date: Available online 9 June 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Stephen L. Morris, Julia Scarisbrick, John Frew J, Clive Irwin, Robert Grieve, Caroline Humber, Aleksandra Kuciejewska, Sally Bayne, Sophie Weatherhead, Fiona Child, Mary Wain, Sean Whittaker
IntroductionTSEB is a very effective treatment for mycosis fungoides. Following reports of similar durations of response to lower doses of TSEB a low dose schedule of TSEB was introduced in the UK.MethodsA 2-week protocol of 12Gy in 8 fractions over 2 weeks was agreed, using the Stanford technique. Data was collected prospectively and the results analysed according to the EORTC/ISCL endpoints. Toxicity was scored according to the CTCAEv4.0.Results103 patients received treatment with a median follow up of 20.6 months (range 3.3 to 53 months). 54 patients were stage IB, 33 stage IIB, 12 stage III and 4 stage IV. The median age was 68 (range 26 – 91). The complete response rate was 18%, partial response rate 69%, stable disease 8% and 5% progressed on treatment. In the patients who had a complete response the median time to relapse was 7.3 months. The median response duration was 11.8 months. The median PFS for all patients was 13.2 months. It was significantly longer at 26.5 months in Stage IB patients compared to 11.3 months in Stage IIB patients (p=0.003, HR 2.66) and 10.2 months in stage III patients (p=0.002, HR 4.62). The treatment was well tolerated with lower toxicity than higher dose schedules.ConclusionsThe low dose 12Gy in 8-fraction schedule of TSEB over 2 weeks is well tolerated and is an effective option for patients with mycosis fungoides.

Teaser

30Gy in 20 fractions is the standard schedule of TSEB in the UK for mycosis fungoides with excellent results but causes significant toxicity. Results of a low dose 12Gy in 8 fractions schedule from 3 centres in the UK were prospectively collected. The results show the complete response rate is lower, the overall response rate and response duration are similar, and the toxicity is less making it an effective option for patients.


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Clinical Outcomes of Large Brain Metastases Treated with Neurosurgical Resection and Intraoperative Cesium-131 Brachytherapy: Results of a Prospective Trial

Publication date: Available online 10 June 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Gabriella A. Wernicke, Cole B. Hirschfeld, Andrew W. Smith, Shoshana Taube, Menachem Z. Yondorf, Bhupesh Parashar, Lucy Nedialkova, Fridon Kulidzhanov, Samuel Trichter, Albert Sabbas, Rohan Ramakrishna, Susan Pannullo, Theodore H. Schwartz
BackgroundStudies on adjuvant stereotactic radiosurgery (SRS) to the cavity of resected brain metastases suggest that larger tumors (>2.0 cm) have higher rates of recurrence and radionecrosis (RN). This study assesses the impact of permanent low-dose ¹³¹Cs brachytherapy on local control and RN in patients treated for large brain metastases.MethodsAfter IRB approval, 42 patients with a total of 46 metastases >2.0 cm in preoperative diameter were accrued onto a prospective trial between 2010 and 2015. Patients underwent surgical resection with intra-operative placement of stranded ¹³¹Cs seeds as permanent volume implants in the resection cavity. The primary endpoint was local freedom from progression (FFP). Secondary endpoints included regional and distant FFP, overall survival (OS), and RN rate. Failures between 5 mm and 20 mm from the cavity, as well as dural-based failures, were considered regional. Separate analysis was performed for metastases > 3.0 cm.ResultsOf the 46 metastases, 18 were > 3.0 cm in diameter. The median follow-up period was 11.9 months (range, 0.6 – 51.9 months). Metastases had a median preoperative diameter of 3.0 cm (range, 2.0 – 6.8 cm). Local FFP was 100% for all tumor sizes. Regional recurrences were found in 3/46 (7%) lesions, yielding a 1-year region FFP of 89% (for tumors > 3.0 cm this was 80% (95% CI 54%, 100%). Distant recurrences were found in 19/46 (41%) patients yielding a 1-year distant FFP of 52%. The median OS was 15.1 months with a 1-year OS of 58%. Lesion size was not significantly associated with any endpoint in univariate or multivariate analysis. Radioresistant histology had worse survival (p=0.036). There were no cases of RN.ConclusionIntraoperative ¹³¹Cs brachytherapy is a promising and effective therapy for large brain metastases requiring neurosurgical intervention, which may offer improved local control and lower rates of RN compared with SRS to the resection cavity.

Teaser

Treating brain metastases ≥2 cm with radiation remains a challenge. Results from traditional techniques such as stereotactic radiosurgery are worse with larger lesions compared to smaller lesions. Here we present an alternative technique to treat large brain metastases using neurosurgical resection and intraoperative brachytherapy using a novel radioisotope, Cesium-131. Our study presents evidence that Cesium-131 results in high rates of local control, minimizes the risk of radionecrosis, and represents a safe and effective adjuvant therapy.


http://ift.tt/2t5LwBv

Precision Oncology and Genomically Guided Radiation Therapy, A Report From the ASTRO/AAPM/NCI Precision Medicine Conference

Publication date: Available online 9 June 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): William A. Hall, Carmen Bergom, Reid F. Thompson, Andrew M. Baschnagel, Srinivasan Vijayakumar, Henning Willers, Allen Li, Christopher J. Schultz, George D. Wilson, Catharine M.L. West, Jacek Capala, C. Norman Coleman, Javier F. Torres-Roca, Joanne Weidhaas, Felix Y. Feng
BackgroundPrecision medicine and oncology is rapidly becoming the central principle of cancer management. Radiation oncologists provide a precise and highly personalized oncologic modality. Our speciality will need to fully embrace personalized and genomically guided treatment recommendations or miss an opportunity to improve the outcomes of our patients.MethodsThe American Society for Radiation Oncology (ASTRO), American Association of Physicists in Medicine (AAPM), and National Cancer Institute (NCI), co-sponsored a precision medicine in radiation oncology meeting. At this conference numerous scientist, clinicians, and physicists conveined in June of 2016 at the National Instititues of Health (NIH) to discuss challenges and future directions toward personalized radiation therapy. Various breakout sessions were held to discuss particular components and approaches to the implementation of personalized radiation oncology. This manuscript serves to summarize the genomically guided radiation therapy breakout session.ResultsA summary of exsisting genomic data enabling personalized radiation therapy, ongoing clinical trials, current challenges, and future directions was collected. The group attempted to provide both a current overview of data that radiation oncologists could use to personalize therapy, along with data that is anticipated in the coming years. It seems apparent from the provided review that a considerable opportunity exists to truly bring genomically guided radiation therapy into clinical reality.ConclusionsGenomically guided radiation therapy is a necessity that must be embraced in the coming years. Incorporating this data into treatment recommendations will provide radiation oncologists with a substantial opportunity to improve outcomes for numerous cancer patients. More research focused on this topic is needed to bring genomic signatures into routine standard of care.

Teaser

Radiation therapy is an incredibly precise and increasingly adaptable therapeutic modality. There is a significant amount of data showing that genomic metrics can significantly influence the outcomes for numerous malignancies treated with radiation therapy. Despite this, current standards of care do little to adapt radiation therapy based on genomic or tumor specific biological factors. This manuscript summarizes the current state of integrating genomic and biologic data into management strategies with radiation therapy.


http://ift.tt/2s7ZXbl

The results of Low dose Total Skin Electron Beam Radiotherapy (TSEB), in patients with mycosis fungoides from the UK cutaneous lymphoma group

Publication date: Available online 9 June 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Stephen L. Morris, Julia Scarisbrick, John Frew J, Clive Irwin, Robert Grieve, Caroline Humber, Aleksandra Kuciejewska, Sally Bayne, Sophie Weatherhead, Fiona Child, Mary Wain, Sean Whittaker
IntroductionTSEB is a very effective treatment for mycosis fungoides. Following reports of similar durations of response to lower doses of TSEB a low dose schedule of TSEB was introduced in the UK.MethodsA 2-week protocol of 12Gy in 8 fractions over 2 weeks was agreed, using the Stanford technique. Data was collected prospectively and the results analysed according to the EORTC/ISCL endpoints. Toxicity was scored according to the CTCAEv4.0.Results103 patients received treatment with a median follow up of 20.6 months (range 3.3 to 53 months). 54 patients were stage IB, 33 stage IIB, 12 stage III and 4 stage IV. The median age was 68 (range 26 – 91). The complete response rate was 18%, partial response rate 69%, stable disease 8% and 5% progressed on treatment. In the patients who had a complete response the median time to relapse was 7.3 months. The median response duration was 11.8 months. The median PFS for all patients was 13.2 months. It was significantly longer at 26.5 months in Stage IB patients compared to 11.3 months in Stage IIB patients (p=0.003, HR 2.66) and 10.2 months in stage III patients (p=0.002, HR 4.62). The treatment was well tolerated with lower toxicity than higher dose schedules.ConclusionsThe low dose 12Gy in 8-fraction schedule of TSEB over 2 weeks is well tolerated and is an effective option for patients with mycosis fungoides.

Teaser

30Gy in 20 fractions is the standard schedule of TSEB in the UK for mycosis fungoides with excellent results but causes significant toxicity. Results of a low dose 12Gy in 8 fractions schedule from 3 centres in the UK were prospectively collected. The results show the complete response rate is lower, the overall response rate and response duration are similar, and the toxicity is less making it an effective option for patients.


http://ift.tt/2t62boB

Brutońs tyrosine kinase (BTK) as a promising target in solid tumors

Publication date: Available online 9 June 2017
Source:Cancer Treatment Reviews
Author(s): J. Molina-Cerrillo, T. Alonso-Gordoa, P. Gajate, E. Grande
Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors.



http://ift.tt/2rbR7K1

Extreme Hypofractionation for High Risk Prostate Cancer: Dosimetric Correlations with Rectal Bleeding

Publication date: Available online 9 June 2017
Source:Practical Radiation Oncology
Author(s): Glenn Bauman, Jeff Chen, George Rodrigues, Melanie Davidson, Andrew Warner, Andrew Loblaw
BackgroundWe explored the association of dosimetric parameters with late rectal bleeding among high risk prostate cancer patients treated with hypofactionated simultaneous in-field boost (H-SIB) to prostate with nodal treatment..MethodologyRectal toxicity results and dose volume histogram (DVH) information from patients treated on TRIAL 1 and TRIAL 2 were combined. Patients in both trials received long term androgen deprivation and H-SIB with prescription dose 40Gy to the prostate and proximal seminal vesicles and 25Gy to the lymph nodes delivered over 5 weekly fractions using image guidance with cone-beam CT. Mean rectal DVH values at 5Gy intervals and mean DVH curves were compared between patients with rectal bleeding (B) versus no bleeding (NB).ResultsThere were 12 B and 33 NB patients in the pooled group. Rectal bleeding was more frequent and of higher grade among TRIAL 1 patients (8/15, 5 Grade 2 or higher) than TRIAL 2 patients (4/30, all Grade 1). For any bleeding (Grade≥1) individual dose volume points in the 20–40Gy range were significantly different (two-sided p<0.05) between the B and NB groups with the 40Gy point being the most significant: V40=1.53%, SD 1.32 (B) vs. 0.69%, SD 1.46 (NB), p=0.006. For Grade≥2 bleeding, the V20Gy was most significant with 68.4%, SD 4.76 (B) vs. 40.4 5%, SD 13.9 (NB), p<0.001.ConclusionsThe higher relative dose volumes to the rectum (V20-V40) were most strongly associated with clinically significant bleeding in this analysis and is consistent with findings of series using H-SIB to treat prostate only. Differences in the prostate target volumes and planning margins likely account for different rates and grades of rectal bleeding observed between trials.



http://ift.tt/2r4TRF3

Extreme Hypofractionation for High Risk Prostate Cancer: Dosimetric Correlations with Rectal Bleeding

Publication date: Available online 9 June 2017
Source:Practical Radiation Oncology
Author(s): Glenn Bauman, Jeff Chen, George Rodrigues, Melanie Davidson, Andrew Warner, Andrew Loblaw
BackgroundWe explored the association of dosimetric parameters with late rectal bleeding among high risk prostate cancer patients treated with hypofactionated simultaneous in-field boost (H-SIB) to prostate with nodal treatment..MethodologyRectal toxicity results and dose volume histogram (DVH) information from patients treated on TRIAL 1 and TRIAL 2 were combined. Patients in both trials received long term androgen deprivation and H-SIB with prescription dose 40Gy to the prostate and proximal seminal vesicles and 25Gy to the lymph nodes delivered over 5 weekly fractions using image guidance with cone-beam CT. Mean rectal DVH values at 5Gy intervals and mean DVH curves were compared between patients with rectal bleeding (B) versus no bleeding (NB).ResultsThere were 12 B and 33 NB patients in the pooled group. Rectal bleeding was more frequent and of higher grade among TRIAL 1 patients (8/15, 5 Grade 2 or higher) than TRIAL 2 patients (4/30, all Grade 1). For any bleeding (Grade≥1) individual dose volume points in the 20–40Gy range were significantly different (two-sided p<0.05) between the B and NB groups with the 40Gy point being the most significant: V40=1.53%, SD 1.32 (B) vs. 0.69%, SD 1.46 (NB), p=0.006. For Grade≥2 bleeding, the V20Gy was most significant with 68.4%, SD 4.76 (B) vs. 40.4 5%, SD 13.9 (NB), p<0.001.ConclusionsThe higher relative dose volumes to the rectum (V20-V40) were most strongly associated with clinically significant bleeding in this analysis and is consistent with findings of series using H-SIB to treat prostate only. Differences in the prostate target volumes and planning margins likely account for different rates and grades of rectal bleeding observed between trials.



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TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX_TGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEX_TGF-β1si. It was shown that LEX_TGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEX_TGF-β1si (DC_{LEX-TGF-β1si}) more effectively promoted CD4⁺ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DC_{LEX-TGF-β1si} inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DC_{LEX-TGF-β1si} induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEX_TGF-β1si may be used as a promising approach for leukemia immunotherapy.

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TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX_TGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEX_TGF-β1si. It was shown that LEX_TGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEX_TGF-β1si (DC_{LEX-TGF-β1si}) more effectively promoted CD4⁺ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DC_{LEX-TGF-β1si} inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DC_{LEX-TGF-β1si} induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEX_TGF-β1si may be used as a promising approach for leukemia immunotherapy.

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TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX_TGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEX_TGF-β1si. It was shown that LEX_TGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEX_TGF-β1si (DC_{LEX-TGF-β1si}) more effectively promoted CD4⁺ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DC_{LEX-TGF-β1si} inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DC_{LEX-TGF-β1si} induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEX_TGF-β1si may be used as a promising approach for leukemia immunotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2rcdoaL
via IFTTT

TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX_TGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEX_TGF-β1si. It was shown that LEX_TGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEX_TGF-β1si (DC_{LEX-TGF-β1si}) more effectively promoted CD4⁺ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DC_{LEX-TGF-β1si} inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DC_{LEX-TGF-β1si} induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEX_TGF-β1si may be used as a promising approach for leukemia immunotherapy.

http://ift.tt/2rcdoaL

Genetic variability in the regulation of the expression cluster of MDR genes in patients with breast cancer

Abstract

Purpose

We aimed to investigate the association between the polymorphism and expression patterns of multiple drug resistance genes (MDR) in breast cancer (BC).

Materials and methods

The MDR gene expression levels were measured in tumor tissues of 106 breast cancer patients using quantitative real-time PCR. Affymetrix CytoScan™ HD Array chips were used to assess genotypes. Pairwise correlation analysis for ABCB1, ABCC1, ABCC2 and ABCG2 gene expression levels was carried out to reveal co-expression clusters. Associations between SNPs of MDR genes and their preoperative expression levels were assessed using analysis of covariance adjusting for covariates.

Results

The SNPs associated with the expression of the ABCB1, ABCC1, ABCC2 and ABCG2 genes before NAC were detected. In addition, 21 SNPs associated with the expression of four ABC-transporter genes and involved in the expression regulation were identified. Validation in an independent sample confirmed the association between the MDR cluster genes and 11 SNPs.

Conclusions

Four MDR genes: ABCB1, ABCC1, ABCC2 and ABCG2 were shown to form the functional expression cluster in breast tumor. Further studies are required to discover precise mechanisms of the cluster regulation, thereby providing new approaches and targets to combat the development of the MDR phenotype during chemotherapy.

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via IFTTT

TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX_TGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEX_TGF-β1si. It was shown that LEX_TGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEX_TGF-β1si (DC_{LEX-TGF-β1si}) more effectively promoted CD4⁺ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DC_{LEX-TGF-β1si} inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DC_{LEX-TGF-β1si} induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEX_TGF-β1si may be used as a promising approach for leukemia immunotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2rcdoaL
via IFTTT

TGF-β1-silenced leukemia cell-derived exosomes target dendritic cells to induce potent anti-leukemic immunity in a mouse model

Abstract

Tumor-derived exosomes (TEX) can induce a specific antitumor immune response and have been developed as a promising tumor vaccine. Despite promising preclinical data, TEX exhibit relatively low efficacy and limited clinical benefit in clinical trials. In the present study, we investigated whether exosomes from the TGF-β1 silenced L1210 cells (LEX_TGF-β1si) can enhance the efficacy of DC-based vaccines. We silenced TGF-β1 in L1210 cells with a lentiviral shRNA vector and prepared the LEX_TGF-β1si. It was shown that LEX_TGF-β1si can significantly decrease TGF-β1 expression of dendritic cells (DC) and effectively promote their maturation and immune function. In addition, DC pulsed with LEX_TGF-β1si (DC_{LEX-TGF-β1si}) more effectively promoted CD4⁺ T cell proliferation in vitro and Th1 cytokine secretion and induced tumor-specific CTL response. This response was higher in potency compared to that noted by the other two formulations. Moreover, DC_{LEX-TGF-β1si} inhibited tumor growth more efficiently than other formulations did as the preventive or therapeutic tumor vaccine. Accordingly, these findings revealed that DC_{LEX-TGF-β1si} induced a more potent antigen-specific anti-leukemic immunity than DC pulsed with exosomes from non-manipulated L1210 cells. This indicated that the targeting of DC by LEX_TGF-β1si may be used as a promising approach for leukemia immunotherapy.

http://ift.tt/2rcdoaL

Genetic variability in the regulation of the expression cluster of MDR genes in patients with breast cancer

Abstract

Purpose

We aimed to investigate the association between the polymorphism and expression patterns of multiple drug resistance genes (MDR) in breast cancer (BC).

Materials and methods

The MDR gene expression levels were measured in tumor tissues of 106 breast cancer patients using quantitative real-time PCR. Affymetrix CytoScan™ HD Array chips were used to assess genotypes. Pairwise correlation analysis for ABCB1, ABCC1, ABCC2 and ABCG2 gene expression levels was carried out to reveal co-expression clusters. Associations between SNPs of MDR genes and their preoperative expression levels were assessed using analysis of covariance adjusting for covariates.

Results

The SNPs associated with the expression of the ABCB1, ABCC1, ABCC2 and ABCG2 genes before NAC were detected. In addition, 21 SNPs associated with the expression of four ABC-transporter genes and involved in the expression regulation were identified. Validation in an independent sample confirmed the association between the MDR cluster genes and 11 SNPs.

Conclusions

Four MDR genes: ABCB1, ABCC1, ABCC2 and ABCG2 were shown to form the functional expression cluster in breast tumor. Further studies are required to discover precise mechanisms of the cluster regulation, thereby providing new approaches and targets to combat the development of the MDR phenotype during chemotherapy.

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Hormone replacement therapy and breast cancer survival: a systematic review and meta-analysis of observational studies

Abstract

Previous studies on the association between hormone replacement therapy (HRT) and breast cancer survival have yielded mixed results. We aimed to perform a meta-analysis to assess the association with all available studies. Relevant studies were identified by searching PubMed and EMBASE to April 2017. We calculated the summary hazard ratios (HRs) and 95% confidence intervals (CIs) using random-effects models. The dose–response relationship was assessed by random-effects meta-analysis and dose–response meta-regression models. Forty cohort studies and two case–control studies involving 1,756,833 participants were included. The results showed that prediagnosis HRT use was associated with decreased risk of dying from breast cancer (HR = 0.88, 95% CI 0.81–0.97) or any cause (HR = 0.79, 95% CI 0.69–0.90). Postdiagnosis HRT use also showed a beneficial effect on breast cancer survival. In the subgroup analyses, we found that patients who were current users at diagnosis or who received combined hormone therapy before diagnosis seemed to show more benefit from HRT use. In dose–response analysis, we observed a linear relationship between prediagnosis HRT and breast cancer-specific mortality and a 1-year increment in duration of exposure to HRT conferred an HR of 0.99 (95% CI 0.98–1.00) for death from breast cancer. In conclusion, the average effect of HRT use seems not harmful to breast cancer survival. Nevertheless, this effect of HRT use is needed for further assessment.

http://ift.tt/2s7nokO

Genetic variability in the regulation of the expression cluster of MDR genes in patients with breast cancer

Abstract

Purpose

We aimed to investigate the association between the polymorphism and expression patterns of multiple drug resistance genes (MDR) in breast cancer (BC).

Materials and methods

The MDR gene expression levels were measured in tumor tissues of 106 breast cancer patients using quantitative real-time PCR. Affymetrix CytoScan™ HD Array chips were used to assess genotypes. Pairwise correlation analysis for ABCB1, ABCC1, ABCC2 and ABCG2 gene expression levels was carried out to reveal co-expression clusters. Associations between SNPs of MDR genes and their preoperative expression levels were assessed using analysis of covariance adjusting for covariates.

Results

The SNPs associated with the expression of the ABCB1, ABCC1, ABCC2 and ABCG2 genes before NAC were detected. In addition, 21 SNPs associated with the expression of four ABC-transporter genes and involved in the expression regulation were identified. Validation in an independent sample confirmed the association between the MDR cluster genes and 11 SNPs.

Conclusions

Four MDR genes: ABCB1, ABCC1, ABCC2 and ABCG2 were shown to form the functional expression cluster in breast tumor. Further studies are required to discover precise mechanisms of the cluster regulation, thereby providing new approaches and targets to combat the development of the MDR phenotype during chemotherapy.

http://ift.tt/2snZZfw

The prognostic effect of estrogen receptor status differs for younger versus older breast cancer patients

Abstract

Purpose

To estimate the prognostic impact of estrogen receptor (ER)-status among women with primary invasive breast cancer, according to age at diagnosis.

Methods

We studied 1910 women with primary invasive breast cancer (stages I–III) who were treated at Women's College Hospital between 1987 and 2000. For each patient, we obtained information on age at diagnosis, tumour size, lymph node status, ER-status, treatments received (radiotherapy, chemotherapy and tamoxifen) and dates and causes of death. Patients were followed from the date of diagnosis until the date of death from breast cancer or the date of last follow-up. We used the Kaplan–Meier method to estimate the 15-year actuarial rates of breast cancer-specific survival for women with ER-positive and ER-negative breast cancer, according to age at diagnosis (categories). We used the Cox proportional hazards model to estimate the adjusted hazard ratios for death from breast cancer associated with positive ER-status (compared to negative ER-status), stratified by age at diagnosis.

Results

We identified 1347 women with ER-positive breast cancer (70.5%) and 563 women with ER-negative breast cancer (29.5%). Among all 1910 women in the cohort, the actuarial rate of breast cancer-specific survival at 15 years was 77% for those with ER-positive breast cancer compared to 70% for those with ER-negative breast cancer (adjusted HR = 0.69; 95% CI 0.56–0.85; p = 0.0006). The prognostic impact of ER-status differed according to age at diagnosis. Among 213 women diagnosed before age 40, breast cancer-specific survival at 15 years was worse for those with ER-positive breast cancer than for those with ER-negative breast cancer (55 vs. 61%; adjusted HR = 0.90; 95% CI 0.57–1.41; p = 0.64). In contrast, among 1697 women diagnosed between ages 40 and 75, breast cancer-specific survival at 15 years was better for those with ER-positive breast cancer than for those with ER-negative breast cancer (78 vs. 72%; adjusted HR = 0.60; 95% CI 0.47–0.76; p < 0.0001).

Conclusions

Positive ER-status is a favourable prognostic factor among women diagnosed with breast cancer at or above age 40, but not among women diagnosed before age 40.

http://ift.tt/2rfZvDK

Osimertinib reactivated immune-related colitis after treatment with anti-PD1 antibody for non-small cell lung cancer

Summary

We reported a case of relapsing immune-related colitis (initially caused by nivolumab) following osimertinib therapy for lung adenocarcinoma. A 45-year-old female who had never smoked was diagnosed with adenocarcinoma of the lung and underwent surgical resection. Four years after surgical resection, she was diagnosed with recurrent disease and was eventually treated with nivolumab as third-line therapy. One month after the completion of nivolumab therapy, the patient reported abdominal pain and frequent diarrhea. We diagnosed immune-related colitis and started oral prednisolone. However, the steroid therapy was ineffective, so the patient was administered infliximab and an increased dose of prednisolone. Her symptoms subsequently resolved, and her mucosal lesions improved. Six months after the last administration of nivolumab, osimertinib was initiated as fourth-line therapy, but 3 days later, the patient developed blood in the stool and frequent diarrhea. Osimertinib treatment was discontinued, given the possibility that it had reactivated the patient's immune-related colitis. We subsequently re-administered oral prednisolone (2 mg/kg/day), and the colitis resolved within a few weeks.

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Osimertinib reactivated immune-related colitis after treatment with anti-PD1 antibody for non-small cell lung cancer

Summary

We reported a case of relapsing immune-related colitis (initially caused by nivolumab) following osimertinib therapy for lung adenocarcinoma. A 45-year-old female who had never smoked was diagnosed with adenocarcinoma of the lung and underwent surgical resection. Four years after surgical resection, she was diagnosed with recurrent disease and was eventually treated with nivolumab as third-line therapy. One month after the completion of nivolumab therapy, the patient reported abdominal pain and frequent diarrhea. We diagnosed immune-related colitis and started oral prednisolone. However, the steroid therapy was ineffective, so the patient was administered infliximab and an increased dose of prednisolone. Her symptoms subsequently resolved, and her mucosal lesions improved. Six months after the last administration of nivolumab, osimertinib was initiated as fourth-line therapy, but 3 days later, the patient developed blood in the stool and frequent diarrhea. Osimertinib treatment was discontinued, given the possibility that it had reactivated the patient's immune-related colitis. We subsequently re-administered oral prednisolone (2 mg/kg/day), and the colitis resolved within a few weeks.

http://ift.tt/2rfYaN1

Xenon as an Adjuvant to Propofol Anesthesia in Patients Undergoing Off-Pump Coronary Artery Bypass Graft Surgery: A Pragmatic Randomized Controlled Clinical Trial.

BACKGROUND: Xenon was shown to cause less hemodynamic instability and reduce vasopressor needs during off-pump coronary artery bypass (OPCAB) surgery when compared with conventionally used anesthetics. As xenon exerts its organ protective properties even in subanesthetic concentrations, we hypothesized that in patients undergoing OPCAB surgery, 30% xenon added to general anesthesia with propofol results in superior hemodynamic stability when compared to anesthesia with propofol alone. METHODS: Fifty patients undergoing elective OPCAB surgery were randomized to receive general anesthesia with 30% xenon adjuvant to a target-controlled infusion of propofol or with propofol alone. The primary end point was the total intraoperative dose of norepinephrine required to maintain an intraoperative mean arterial pressure >70 mm Hg. Secondary outcomes included the perioperative cardiorespiratory profile and the incidence of adverse and serious adverse events. RESULTS: Adding xenon to propofol anesthesia resulted in a significant reduction of norepinephrine required to attain the predefined hemodynamic goals (cumulative intraoperative dose: median [interquartile range]: 370 [116-570] vs 840 [335-1710] [micro]g, P = .001). In the xenon-propofol group, significantly less propofol was required to obtain a similar depth of anesthesia as judged by clinical signs and the bispectral index (propofol effect site concentration [mean +/- SD]: 1.8 +/- 0.5 vs 2.8 +/- 0.3 mg, P

http://ift.tt/2r57p3g

Perioperative Temperature Measurement Considerations Relevant to Reporting Requirements for National Quality Programs Using Data From Anesthesia Information Management Systems.

Background: Perioperative hypothermia may increase the incidences of wound infection, blood loss, transfusion, and cardiac morbidity. U.S. national quality programs for perioperative normothermia specify the presence of at least 1 "body temperature" >=35.5[degrees]C during the interval from 30 minutes before to 15 minutes after the anesthesia end time. Using data from 4 academic hospitals, we evaluated timing and measurement considerations relevant to the current requirements to guide hospitals wishing to report perioperative temperature measures using electronic data sources. METHODS: Anesthesia information management system databases from 4 hospitals were queried to obtain intraoperative temperatures and intervals to the anesthesia end time from discontinuation of temperature monitoring, end of surgery, and extubation. Inclusion criteria included age >16 years, use of a tracheal tube or supraglottic airway, and case duration >=60 minutes. The end-of-case temperature was determined as the maximum intraoperative temperature recorded within 30 minutes before the anesthesia end time (ie, the temperature that would be used for reporting purposes). The fractions of cases with intervals >30 minutes between the last intraoperative temperature and the anesthesia end time were determined. RESULTS: Among the hospitals, averages (binned by quarters) of 34.5% to 59.5% of cases had intraoperative temperature monitoring discontinued >30 minutes before the anesthesia end time. Even if temperature measurement had been continued until extubation, averages of 5.9% to 20.8% of cases would have exceeded the allowed 30-minute window. Averages of 8.9% to 21.3% of cases had end-of-case intraoperative temperatures

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Anesthetic and Obstetric Management of Syringomyelia During Labor and Delivery: A Case Series and Systematic Review.

BACKGROUND: Syringomyelia is a rare, slowly progressive neurological condition characterized by the presence of a syrinx within the spinal cord. Consensus regarding the safest mode of delivery and anesthetic management in patients with syringomyelia remains controversial and presents management dilemmas. This study reviews the cases of syringomyelia at our institution and provides a systematic review of the literature to guide decisions regarding labor and delivery management. METHODS: A retrospective review of cases at our hospital from 2002 to 2014 and a systematic review of the literature from 1946 to 2014 were undertaken. Hospital records and electronic databases were interrogated using International Classification of Diseases, 10th Revision codes and the keywords "syringomyelia," "syringobulbia," and "pregnancy". Data regarding demographics, diagnosis, radiology reports, neurological symptoms, mode of delivery, anesthetic management, and maternal-fetal outcomes were collected. RESULTS: We collected and analyzed data on a total of 43 pregnancies in 39 patients. The most common location for syrinx was in the cervicothoracic region (41.9%). The large majority of patients (n = 34; 87%) demonstrated signs and symptoms associated with syringomyelia before delivery. Syringomyelia associated with Arnold Chiari malformation was documented in 49% (n = 21) cases. General anesthesia was the most commonly used (n = 21/30, 70%) anesthetic technique for cesarean delivery. The majority (n = 9/13, 69%) of patients had an epidural sited for labor analgesia. There were no maternal or neonatal complications associated with neuraxial anesthesia; however, 3 cases (14%) raised concerns regarding general anesthesia including difficult intubation, transient worsening of neurological symptoms postpartum, and prolonged muscle paralysis after atracurium. CONCLUSIONS: Despite concerns regarding aggravation of the syrinx with vaginal delivery, this mode of delivery has never caused any documented long-term worsening of neurological condition. All techniques of anesthesia have been performed successfully without major lasting complications. All cases necessitate patient counseling and individualized multidisciplinary involvement to ensure maternal safety. (C) 2017 International Anesthesia Research Society

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Protective Lung Ventilation and Morbidity After Pulmonary Resection: A Propensity Score-Matched Analysis.

BACKGROUND: Protective lung ventilation (PLV) during one-lung ventilation (OLV) for thoracic surgery is frequently recommended to reduce pulmonary complications. However, limited outcome data exist on whether PLV use during OLV is associated with less clinically relevant pulmonary morbidity after lung resection. METHODS: Intraoperative data were prospectively collected in 1080 patients undergoing pulmonary resection with OLV, intentional crystalloid restriction, and mechanical ventilation to maintain inspiratory peak airway pressure =8 mL/kg (predicted body weight) mean tidal volume. The primary outcome was the occurrence of pneumonia and/or acute respiratory distress syndrome (ARDS). Propensity score matching was used to generate PLV and non-PLV groups with comparable characteristics. Associations between outcomes and PLV status were analyzed by exact logistic regression, with matching as cluster in the anatomic and nonanatomic lung resection cohorts. RESULTS: In the propensity score-matched analysis, the incidence of pneumonia and/or ARDS among patients who had an anatomic lung resection was 9/172 (5.2%) in the non-PLV compared to the PLV group 7/172 (4.1%; odds ratio, 1.29; 95% confidence interval, 0.48-3.45, P= .62). The incidence of pneumonia and/or ARDS in patients who underwent nonanatomic resection was 3/118 (2.5%) in the non-PLV compared to the PLV group, 1/118 (0.9%; odds ratio, 3.00; 95% confidence interval, 0.31-28.84, P= .34). CONCLUSIONS: In this prospective observational study, we found no differences in the incidence of pneumonia and/or ARDS between patients undergoing lung resection with tidal volumes =8 mL/kg. Our data suggest that when fluid restriction and peak airway pressures are limited, the clinical impact of PLV in this patient population is small. Future randomized trials are needed to better understand the benefits of a small tidal volume strategy during OLV on clinically important outcomes. (C) 2017 International Anesthesia Research Society

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Improving Performance by Monitoring the Success Rate of Peripheral Nerve Blocks.

In our hospital, we introduced a system to measure the collective and individual efficacy of brachial plexus and popliteal nerve blocks with the objective to create transparency as an instrument for monitoring and improvement. Initially, individual results were anonymous, but after 1 year anonymity was lifted within the team of anesthesiologists and results are now discussed quarterly. Collective performance of interscalene, supraclavicular, and popliteal blocks improved significantly over time. Sharing and discussing collective and individual performance has resulted in critical self-appraisal and increased willingness to learn from each other and strengthened the team's ambition for further improvement. (C) 2017 International Anesthesia Research Society

http://ift.tt/2r52S0V