CD126 and targeted therapy with Tocilizumab in Chronic Lymphocytic Leukemia

Purpose: Experimental Design:The levels of membrane-bound CD126 expression were determined on freshly isolated CLL B-cells (n=58) using flow cytometry. These CLL cells were treated with Chlorambucil (CBL) or Fludarabine with or without anti-CD126 antibody Tocilizumab for 24 hours and IL-6-mediated STAT3 transcriptional activity and cell cycle alteration were evaluated. Results: CD126 surface expression was found in all cases and positively correlated with the levels of in vivo constitutive STAT3 activity. The levels of CD126 expression were significantly and positively correlated with the resistance of CLL cells to in vitro treatment with CBL or Fludarabine and poor in vivo treatment response of CLL patients. Blocking IL-6 signaling with the anti-CD126 antibody, Tocilizumab, had profound effects on STAT3-mediated survival and growth signals: decreased Mcl-1 and Bcl-xL, favoring an apoptotic profile; and decreased p27 with increased cyclin E and CDK2 expression, leading to cell cycle shift from G0 to G1. These Tocilizumab-mediated changes induced chemo-sensitization in resistant CLL cells, with the greatest effect seen in cells with higher CD126 expression (P<0.001). Conclusions: CLL cells with higher CD126 expression are more resistant to treatment in vivo and in vitro via IL-6-CD126-STAT3 axis. Blockade CD126 using Tocilizumab sensitizes CLL cells to chemotherapy.

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Systemic Correlates of White Adipose Tissue Inflammation in Early-Stage Breast Cancer

Purpose: Obesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance. Experimental Design: WAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures of the breast (CLS-B). Two independent groups were examined in cross-sectional (Cohort 1) and retrospective (Cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n=10) or treatment (n=90). Metabolic syndrome-associated circulating factors were compared by CLS-B status. The association between CLS-B and the metabolic syndrome was validated in Cohort 2 which included 127 women who developed metastatic breast cancer. Distant recurrence free survival (dRFS) was compared by CLS-B status. Results: In Cohorts 1 and 2, breast WAT inflammation was detected in 52/100 (52%) and 52/127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and interleukin-6; and lower HDL cholesterol and adiponectin (P<0.05) in Cohort 1. In Cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P<0.05). Compared to patients without breast WAT inflammation, the adjusted hazard ratio for dRFS was 1.83 (95% CI, 1.07 to 3.13) for patients with inflammation. Conclusions: WAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis.

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Effective clinical responses in metastatic melanoma patients after vaccination with primary myeloid dendritic cells

PURPOSE Thus far, dendritic cell (DC)-based immunotherapy of cancer was primarily based on in vitro-generated monocyte-derived DCs, which require extensive in vitro manipulation. Here, we report on a clinical study exploiting primary CD1c+ myeloid DCs, naturally circulating in the blood. EXPERIMENTAL DESIGN Fourteen stage IV melanoma patients, without previous systemic treatment for metastatic disease, received autologous CD1c+ myeloid DCs, activated by only brief (16h) ex vivo culture and loaded with tumor associated antigens of tyrosinase and gp100. RESULTS Our results show that therapeutic vaccination against melanoma with small amounts (3-10x106) of myeloid DCs is feasible and without substantial toxicity. Four out of fourteen patients showed long-term progression-free survival (12-35 months), which directly correlated with the development of multifunctional CD8+ T cell responses in three of these patients. In particular, high CD107a expression, indicative for cytolytic activity, and IFN as well as tumor necrosis factor (TNF)α and CCL4 production was observed. Apparently, these T cell responses are essential to induce tumor regression and promote long-term survival by stalling tumor growth. CONCLUSION We show that vaccination of metastatic melanoma patients with primary myeloid DCs is feasible and safe and results in induction of effective anti-tumor immune responses that coincide with improved progression-free survival.

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Blocking HSP90 addiction inhibits tumor cell proliferation, metastasis development and synergistically acts with zoledronic acid to delay osteosarcoma progression.

Purpose:Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants the development of new strategies to improve overall patient survival. Among them, HSP90 is a molecular chaperone involved in the maturation and stability of various oncogenic proteins leading to tumor cells survival and disease progression. We assessed the antitumor properties of a synthetic HSP90 inhibitor, PF4942847, alone or in combination with zoledronic acid in osteosarcoma. Experimental Design:The effects of PF4942847 were evaluated on human osteosarcoma cells growth and apoptosis. Signaling pathways were analyzed by western blotting. The consequence of HSP90 therapy combined or not with zoledronic acid was evaluated in mice bearing HOS-MNNG xenografts on tumor growth, associated-bone-lesions and pulmonary metastasis. The effect of PF4942847 on osteoclastogenesis was assessed on human CD14+ monocytes. Results:In osteosarcoma cell lines, PF4942847 inhibited cell growth in a dose-dependent manner (IC50 ±50nM) and induced apoptosis with an increase of sub-G1 fraction and cleaved-PARP. These biologic events were accompanied by decreased expression of Akt, p-ERK, C-Met and C-RAF1. When administered orally to mice bearing osteosarcoma tumors, PF4942847 significantly inhibited tumor growth by 80%, prolonged survival compared to controls, and inhibited pulmonary metastasis by blocking c-Met, FAK and MMP9 signaling. In contrast to 17-AAG, PF4942847 didn't induce osteoclast differentiation, and synergistically acted with zoledronic acid to delay osteosarcoma progression and prevent bone lesions. Conclusions:All these data provide a strong rationale for clinical evaluation of PF4942847 alone or in combination with zoledronic acid in osteosarcoma.

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Surgical Guidance in Prostate Cancer: "From Molecule to Man" Translations

Given the frequency of the disease and the difficulty of tumor resections, image-guided surgery technologies may aid the surgical management of prostate cancer patients. The "from molecule to man" translation of such approaches is, however, complex and depends on many different features, both from a technical and a practical perspective.

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Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is a member of the fibroblast growth factor receptor tyrosine kinase family. It has been identified as a promising therapeutic target in multiple types of cancer. We have investigated FGFR3 protein expression and FGFR3 gene copy-numbers in a single well-documented cohort of oral and oropharyngeal squamous cell carcinoma. Tissue microarray sets containing 452 formalin-fixed paraffin-embedded tissues were immunohistochemically stained with an anti-FGFR3 antibody and hybridized with a FGFR3 fluorescence in situ hybridization probe. FGFR3 protein expression was correlated with clinicopathological and survival data, which were retrieved from electronic medical records. FGFR3 mRNA data of 522 head and neck squamous cell carcinoma (HNSCC) were retrieved from The Cancer Genome Atlas (TCGA). Fibroblast growth factor receptor 3 (FGFR3) protein was overexpressed in 48% (89/185) of oral and 59% (124/211) of oropharyngeal squamous cell carcinoma. Overexpression of FGFR3 protein was not related to overall survival or disease-free survival in oral (HR[hazard ratio]: 0.94; 95% CI: 0.64–1.39; P = 0.77, HR: 0.94; 95% CI: 0.65–1.36; P = 0.75) and oropharyngeal squamous cell carcinoma (HR: 1.21; 95% CI: 0.81–1.80; P = 0.36, HR: 0.42; 95% CI: 0.79–1.77; P = 0.42). FGFR3 mRNA was upregulated in 3% (18/522) of HNSCC from the TCGA. The FGFR3 gene was gained in 0.6% (1/179) of oral squamous cell carcinoma but no amplification was found in oral and oropharyngeal squamous cell carcinoma. In conclusion, FGFR3 protein is frequently overexpressed in oral and oropharyngeal squamous cell carcinoma. Therefore, it may serve as a potential therapeutic target for FGFR3-directed therapies in oral and oropharyngeal squamous cell carcinoma.

FGFR3 is frequently aberrated in HPV-positive head and neck cancers and it has been identified as a candidate therapeutic target. Here, we show that FGFR3 protein is frequently overexpressed in oral and oropharyngeal cancer.

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Functional MRI evidence for the decline of word retrieval and generation during normal aging

Abstract

This fMRI study aimed to explore the effect of normal aging on word retrieval and generation. The question addressed is whether lexical production decline is determined by a direct mechanism, which concerns the language operations or is rather indirectly induced by a decline of executive functions. Indeed, the main hypothesis was that normal aging does not induce loss of lexical knowledge, but there is only a general slowdown in retrieval mechanisms involved in lexical processing, due to possible decline of the executive functions. We used three tasks (verbal fluency, object naming, and semantic categorization). Two groups of participants were tested (Young, Y and Aged, A), without cognitive and psychiatric impairment and showing similar levels of vocabulary. Neuropsychological testing revealed that older participants had lower executive function scores, longer processing speeds, and tended to have lower verbal fluency scores. Additionally, older participants showed higher scores for verbal automatisms and overlearned information. In terms of behavioral data, older participants performed as accurate as younger adults, but they were significantly slower for the semantic categorization and were less fluent for verbal fluency task. Functional MRI analyses suggested that older adults did not simply activate fewer brain regions involved in word production, but they actually showed an atypical pattern of activation. Significant correlations between the BOLD (Blood Oxygen Level Dependent) signal of aging-related (A > Y) regions and cognitive scores suggested that this atypical pattern of the activation may reveal several compensatory mechanisms (a) to overcome the slowdown in retrieval, due to the decline of executive functions and processing speed and (b) to inhibit verbal automatic processes. The BOLD signal measured in some other aging-dependent regions did not correlate with the behavioral and neuropsychological scores, and the overactivation of these uncorrelated regions would simply reveal dedifferentiation that occurs with aging. Altogether, our results suggest that normal aging is associated with a more difficult access to lexico-semantic operations and representations by a slowdown in executive functions, without any conceptual loss.

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Approval of Osimertinib and Necitumumab Increases Lung Cancer Treatment Options

Last month, the Food and Drug Administration (FDA) approved two targeted therapies for patients with advanced non-small cell lung cancer (NSCLC).

The agency approved osimertinib (Tagrisso™) for patients who have developed the epidermal growth factor receptor (EGFR) T790M mutation in their tumors after prior treatment with an EGFR-targeted therapy, and necitumumab (Portrazza™), in combination with standard chemotherapy drugs, for the initial treatment of patients with metastatic squamous NSCLC.

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MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK

Abstract

Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib.

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A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck

Abstract

DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (P _trend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02–1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3′-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.

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The clinicopathologic differences of central lymph node metastasis in predicting lateral lymph node metastasis and prognosis in papillary thyroid cancer associated with or without Hashimoto’s thyroiditis

Abstract

This study aims to evaluate the difference of central lymph node metastases (LNM) in papillary thyroid carcinoma (PTC) associated with or without Hashimoto's thyroiditis (HT) in predicting lateral node metastasis. A retrospective case control study was performed. Patients (1276) with PTC who underwent a total or near-total thyroidectomy with at least one lymph node dissection in our institution were retrospectively reviewed. All patients were divided into two groups (HT-group and non-HT group) according to the pathological diagnosis. In HT-group, the incidence of both central and lateral LNM was lower compared with non-HT group. The average of central metastatic lymph node radio (LNR) was also lower than that in Non-HT group. The multivariate analysis showed that the number of metastatic central LNs (HT ≥ 4, Non-HT ≥ 2) and the central LNR (HT ≥ 0.4, Non-HT ≥ 0.6) were independently associated with lateral LNM. Patients with HT need larger primary tumor size, more positive central LN and higher LNR to predict the presence of lateral LNM. HT may protect against central and lateral LNM in PTC. The number of positive central LNs and central LNR in PTC could be used to determine the presence of lateral LNM and inform postoperative follow-up.

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Protective effects of mito-TEMPO against doxorubicin cardiotoxicity in mice

Abstract

Purpose

Doxorubicin (DOX) is a chemotherapeutic that is widely used for the treatment of many human tumors. However, the development of cardiotoxicity has limited its use. The aim of the present study was to evaluate the possible efficacy of mito-TEMPO (mito-T) as a protective agent against DOX-induced cardiotoxicity in mice.

Methods

C57BL/6 mice were treated twice with mito-T at low (5 mg/kg body weight) or high (20 mg/kg body weight) dose and once with DOX (24 mg/kg body weight) or saline (0.1 mL/20 g body weight) by means of intraperitoneal injections. The levels of malondialdehyde (MLDA), a marker of lipid peroxidation, and serum levels of creatine kinase were evaluated 48 h after the injection of DOX.

Results

DOX induced lipid peroxidation in heart mitochondria (p < 0.001), and DOX-treated mice receiving mito-T at low dose had levels of MLDA significantly lower than the mice that received only DOX (p < 0.01). Furthermore, administration of mito-T alone did not cause any significant changes from control values. Additionally, DOX-treated mice treated with mito-T at high dose showed decrease in serum levels of total CK compared to mice treated with DOX alone (p < 0.05).

Conclusion

Our results indicate that mito-T protects mice against DOX-induced cardiotoxicity.

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HPV detection-based cervical cancer screening program in low-resource setting: lessons learnt from a community-based demonstration project in India

Abstract

Purpose

A demonstration project was conducted to assess feasibility of implementing HPV detection-based cervical cancer screening in primary care settings in India and to generate local evidence on feasibility and effectiveness of HPV detection in primary screening.

Methods

The project was implemented by setting up screening clinics at primary health centers. Eligible women were screened by HPV DNA test (Hybrid capture 2). All samples were processed and tested in a single laboratory. Colposcopy services were provided to screen-positive women at the same community clinics. Project utilized services of community health workers for community mobilization, recall of screen-positive and disease-positive women. Women with ≥CIN2 diagnosis were treated at tertiary hospital.

Results

Totally, 44,110 women were screened and HPV positivity was 4.7 %. Compliance to recall of HC2-positive women for colposcopy was 78 %. Detection rate of CIN3+ by HPV test was 3.9/1,000 women. Compliance of women to treatment was 80.1 %. However, compliance of HPV-positive women for follow-up at 1 year was poor (23.2 %). Concurrent use of VIA to screen the women did not have any advantage but increased number of unnecessary colposcopies and biopsies.

Conclusions

Our project demonstrated that it was possible to implement HPV detection-based screening using existing primary healthcare infrastructure. Performing colposcopy at primary setting is feasible, improves compliance and reduces over-treatment. In settings with low to moderately high HPV prevalence, direct referral of HPV-positive women is advisable. Community health workers can be effectively used for recalling the positive women.

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UDP-glucuronosyltransferase 1A1*6 and *28 polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer

Abstract

Background

Irinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety.

Methods

All data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia.

Results

A total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.which are associated with a decrease in the8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m², respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16–2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22–4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24–2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05–3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08–2.18; p = 0.0176) were also identified as significant risk factors.

Conclusion

The risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.

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Imaging strategy for response evaluation to chemoradiotherapy of the nodal disease in patients with head and neck squamous cell carcinoma

Abstract

Background

Definitive chemoradiotherapy (CRT) is used to treat lymph node metastatic head and neck cancer patients. Regional control of the neck disease is important to improve the prognosis, and the accuracy of the method used to evaluate the metastatic lymph node(s) after CRT is crucial to the decision-making process for any following salvage surgery.

Methods

Patients undergoing CRT were divided in two groups of patients of those showing complete clinical response (CR) and those showing clinical non-response (non-CR), as assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI), ultrasonography, fluorodeoxyglucose-positron emission tomography (FDG-PET), and fine needle aspiration cytology. The responses (CR vs. non-CR) were compared with the actual clinical outcomes. For the interim analysis, the study period was broken down into two periods, namely, the exploratory phase (patients treated between January 2002 and April 2012) and the validating phase (patients treated between May 2012 and January 2014).

Results

The sensitivity, specificity, and accuracy were as follows: CT and/or MRI, 66.7, 73.8, and 72.8 %, respectively, in the exploratory phase; ultrasonography, 91.7, 70.6, and 73.4 %, respectively, in the exploratory phase and 80.0, 82.8, and 82.4 %, respectively, in the validating phase; FDG-PET, 50.0, 97.5, and 91.3 %, respectively, in the exploratory phase and 60.0, 100, and 94.1 %, respectively, in the validating phase; cytology, 68.4, 95.9, and 90.3 %, respectively, in the exploratory phase and 66.7, 100, and 85.7 %, respectively, in the validating phase.

Conclusions

Based on our results, CT and/or MRI appear to be inadequate methods for the evaluation of the response of lymph node(s) to CRT. In contrast, ultrasonography appears to be a highly sensitive and useful tool for positive screening at 6–8 weeks after CRT, and FDG-PET appears to be a highly specific and useful tool for negative screening at 8–12 weeks after CRT.

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Incidence of stroke and stroke subtypes in chronic obstructive pulmonary disease

Abstract

It is uncertain whether the incidence of stroke is increased in patients with chronic obstructive pulmonary disease (COPD), and whether COPD is associated with all subtypes of stroke (i.e. ischemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage). We evaluated the association between COPD and incidence of stroke in a nation-wide cohort study. All individuals between 40 and 84 years of age, hospitalised for COPD between 1987 and 2003 in Sweden were identified in the Swedish hospital discharge register. For each COPD patient (n = 103,419), one reference individual was randomly selected from the general population matched for year of birth, sex and county of residence. After excluding subjects with prior stroke, incidence rates during 10 years follow-up were calculated. Hazard ratios (HR) for stroke comparing COPD patients with reference subjects were estimated using Cox regression adjusting for demographics and comorbidities. Incidence of all-cause stroke (n events = 17,402) was significantly increased in COPD patients compared to reference individuals (HR 1.24, 95 % CI 1.19–1.28), especially during the first 2 years after COPD diagnosis (HR 1.46, 1.37–1.55). Incidences of ischemic stroke (HR 1.20, 1.15–1.25), intracerebral haemorrhage (HR 1.29, 1.16–1.43) and subarachnoid haemorrhage (HR 1.46, 1.16–1.85) were all increased in COPD patients. Incidences of all stroke subtypes are increased in COPD, especially during the first years after COPD diagnosis. The association was independent of several comorbidities, although residual confounding from smoking and hypertension cannot be excluded. A global evaluation of stroke risk factors seems warranted in patients with COPD.

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Oncogenic roles of carbonic anhydrase 8 in human osteosarcoma cells

Abstract

Carbonic anhydrase 8 (CA8), a member of the carbonic anhydrase family, is one of the three isozymes that do not catalyze the reversible hydration of carbon dioxide due to the lack of one important histidine. In the present study, we observed increased expression of CA8 in more aggressive types of human osteosarcoma (OS) cells and found that CA8 expression is correlated with disease stages, such that more intense expression occurs in the disease late stage. We also demonstrated that overexpression of CA8 in human OS (HOS) cells significantly increased cell proliferation both in vitro and in vivo. Downregulated CA8 sensitized cells to apoptotic stress induced by staurosporine and cisplatin, suggesting a specific role of CA8 to protect cells from stresses. In addition, downregulation of CA8 in HOS cells reduced cell invasion and colony formation ability in soft agar and further decreased matrix metalloproteinase 9 and focal adhesion kinase expression, indicating that CA8 might facilitate cancer cell invasion via the activation of FAK-MMP9 signaling. Interestingly, HOS cells with CA8 knockdown showed a significant decrease in glycolytic activity and cell death under glucose withdrawal, further indicating that CA8 may be involved in regulating aerobic glycolysis and enhancing cell viability. Knockdown of CA8 significantly decreased phosphorylated Akt expression suggesting that the oncogenic role of CA8 may be mediated by the regulation of Akt activation through p-Akt induction. Importantly, the inhibition of glycolysis by 2-deoxyglucose sensitized CA8 HOS-CA8-myc cells to cisplatin treatment under low glucose condition, highlighting a new therapeutic option for OS cancer.

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HLA-DP is the cervical cancer susceptibility loci among women infected by high-risk human papillomavirus: potential implication for triage of human papillomavirus-positive women

Abstract

Given that only a small proportion of women infected by high-risk human papillomavirus (hrHPV) develop cervical cancer, it's important to identify biomarkers for distinguishing women with hrHPV positivity who might develop cervical cancer from the transient infections. In this study, we hypothesized that human leukocyte antigens (HLA) susceptibility alleles might contribute to cervical cancer risk among females infected by hrHPV, and interact with hrHPV types. A case-control study with 593 cervical cancer cases and 407 controls (all hrHPV positive) was conducted to evaluate the effect of eight HLA-related single-nucleotide polymorphisms (SNPs) and their interactions with hrHPV types on the risk of cervical cancer. Three HLA-DP SNPs (rs4282438, rs3117027, and rs3077) were found to be significantly associated with risk of cervical cancer (rs4282438: odds ratio (OR) = 0.72, 95 % confidence interval (CI) = 0.56–0.93; rs3117027: OR = 1.41, 95 % CI = 1.10–1.83; and rs3077: OR = 1.37, 95 % CI = 1.04–1.80) among women infected with hrHPV. An additive interaction between HPV16 and rs4282438 for cervical cancer risk was also found (P _{for interaction} = 0.002). Compared with subjects carrying variant genotypes (GG/TG) and non-HPV16 infections, those carrying wild-type genotype (TT) of rs4282438 and HPV16 positive had a 5.22-fold increased risk of cervical cancer (95 % CI = 3.39–8.04). Our study supported that certain HLA-DP alleles in concert with HPV16 could have a predisposition for cervical cancer development, which may be translated for triage of hrHPV-positive women.

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MiR-205 functions as a tumor suppressor in adenocarcinoma and an oncogene in squamous cell carcinoma of esophagus

Abstract

Esophageal cancer is a malignant disease with poor prognosis, increasing incidence, and ineffective treatment options. MicroRNAs are post-transcriptional regulators of gene expression involved in many biological processes including carcinogenesis. We determined miR-205 expression levels in tumor/non-tumor tissues of 45 esophageal cancer patients using qPCR and found that decreased level of miR-205 in tumor tissue correlates with poor overall survival in esophageal adenocarcinoma patients. Further, we observed significantly higher levels of miR-205 in tumor tissue of esophageal squamous cell carcinoma. Ectopic overexpression of miR-205 in adenocarcinoma cell line SK-GT-4 led to decreased cell proliferation, cell cycle arrest in G1, and decreased migration ability. Conversely, in squamous cell line KYSE-150, same effects like inhibition of proliferation, migration, and colony-forming potential and cell cycle arrest in G2 were observed after silencing of miR-205. We performed global gene expression profiling and revealed that suppressive functioning of miR-205 in adenocarcinoma could be realized through regulation of epithelial-mesenchymal transition (EMT), whereas oncogenic in squamous cell carcinoma by regulation of metalloproteinase 10. Our results suggest that miR-205 could serve as biomarker in esophageal cancer and acts as a tumor suppressor in esophageal adenocarcinoma and oncogene in esophageal squamous cell carcinoma.

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Heat shock protein 27 and gross cystic disease fluid protein 15 play critical roles in molecular apocrine breast cancer

Abstract

Molecular apocrine breast cancer (MABC) has a distinct hormonal profile, being estrogen receptor (ER) and progesterone receptor (PR) negative but androgen receptor (AR) positive. The clinical significance of MABC and its relative variables have not been absolutely clarified and remain to be determined. Five hundred cases of invasive breast carcinoma were randomly selected in this study, including 158 MABC cases and 342 nonMABC cases. Expression of ER, PR, epidermal growth factor receptor 2 (HER2), Ki67, AR, gross cystic disease fluid protein 15 (GCDFP15), and heat shock protein 27 (HSP27) were analyzed by immunohistochemistry. Differences of continuous variables between MABC and nonMABC subgroups were evaluated by the chi-square test. The Kaplan–Meier method was performed to evaluate disease-free survival (DFS) and overall survival (OS). The MABC subgroup had higher histological grade, bigger tumor size, more lymph node metastasis, and higher pTNM stage than the nonMABC subgroup (P < 0.05), and patients with MABC had poorer prognosis than those of the nonMABC subgroup (P < 0.05). Both GCDFP15 and HSP27 were expressed differently in the MABC and nonMABC subgroups (P < 0.05). Furthermore, in the MABC subgroup, positive HSP27 expression indicated higher risk of recurrence (P < 0.05) and positive GCDFP15 expression was also a poor marker for patient outcome (P < 0.05). MABC patients with HSP27 and GCDFP15 co-expression had worse outcome (P < 0.05). Our data suggested that MABC had a high risk of recurrence. Positive expression of both GCDFP15 and HSP27 were correlated with MABC malignancy. Targeting AR and HSP27 at the same time might offer a useful strategy to MABC.

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Erratum to: The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells

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MiR-130b inhibits proliferation and induces apoptosis of gastric cancer cells via CYLD

Abstract

A role of microRNA-130b (miR-130b) in the carcinogenesis of gastric cancer remains undetermined. In this study, we studied the effects and mechanism of miR-130b to the gastric cell proliferation and apoptosis. We found that the levels of miR-130b significantly up-regulated in gastric cancer tissue, compared to the paired adjacent non-tumor gastric tissue. The miR-130b levels in gastric cancer cell lines were significantly higher than those in control normal gastric tissues. Transfection with the miR-130b mimic enhanced the cell proliferation and suppressed cell apoptosis in gastric cancer cells, while transfection with the anti-sense of miR-130b (anti-miR-130b) suppressed cell proliferation and induced cell apoptosis in gastric cancer cells. Bioinformatics analyses showed that cylindromatosis gene (CYLD) was a potential target gene of miR-130b. The luciferase activity assay and western blot verified that miR-130b targeted CYLD messenger RNA (mRNA) to modulate its protein levels. Together, our study suggests that aberrantly expressed miR-130b may regulate cell apoptosis and proliferation of human gastric cancer cells via CYLD, which appears to be a promising therapeutic target for gastric cancer.

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Immunomodulatory potencies of isolated compounds from Crataegus azarolus through their antioxidant activities

Abstract

The search of natural immunomodulatory agents has become an area of great interest in order to reduce damage to the human body. In this study, the immunomodulatory potential of Crataegus azarolus and its isolated hyperoside on mouse lymphocytes and macrophages in vitro was assessed. The effect of C. azarolus natural compounds on splenocytes proliferation, natural killer (NK) and cytotoxic T lymphocytes (CTL) activities, and on macrophage-mediated cytotoxicity were assessed by MTT test. Phagocytic activity and inhibition of nitric oxide (NO) release by macrophages were also evaluated. The antioxidant capacity of these products was evaluated by determining their cellular antioxidant activity (CAA) in splenocytes and macrophages. Depending on the concentrations, both ethyl acetate (EA) extract and hyperoside (Hyp) from C. azarolus affect macrophage functions by modulating their lysosomal enzyme activity and nitric oxide release. Whereas, the above-mentioned products significantly promote LPS and lectin-stimulated splenocyte proliferation, implying a potential activation of lymphocytes B and T enhancing humoral and cellular immune responses. Moreover, EA extract and Hyp could enhance the activity of NK and T lymphocytes cells, as well as the macrophages-mediated cytotoxicity against B16F10 cells. The anti-inflammatory activity was concomitant with the cellular antioxidant effect of the tested compounds against macrophages and splenocytes. Collectively, C. azarolus and its isolated hyperoside exhibited an immunomodulatory effect through their antioxidant activity. These findings suggest that C. azarolus should be explored as a novel potential immunomodulatory agent for the treatment of inflammatory diseases.

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Oncogenic relevant defensins: expression pattern and proliferation characteristics of human tumor cell lines

Abstract

The objective of this study was to investigate gene expression levels of oncogenic relevant human defensins and their impact on proliferation rates of 29 cell lines derived from main types of different tumor origins. Differential gene expression analysis of human defensins was performed by real-time PCR experiments. The proliferation rate of tumor cells that had been cultivated in the absence or presence of biologically active peptides was analyzed with a lactate dehydrogenase assay kit. At least one member of the defensin family was expressed in each tumor cell line, whereby α-defensin (DEFA1), DEFA2, or DEFA3 transcripts could be ubiquitously detected. Cell lines of neural origin (glioma, neuroblastoma, and small-cell lung carcinoma) expressed far less human β-defensins (hBDs) in comparison to other tumor types. The expression level of a specific defensin in various cell lines could vary by more than five orders of magnitude. Compensatory mechanisms on the expression levels of the different defensins could not be strictly observed. Only in 3 out of 29 tumor cell lines the proliferation rate was affected after defensin stimulation. The variable appearance of defensins, as well as the cell line-restricted functional activity, argues for the integration of defensins in complex cellular and molecular networks that tolerate rather flexible expression patterns.

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A Phase 2 Randomized, Double-Blind, Multicenter Trial of Imexon Plus Gemcitabine Versus Gemcitabine Plus Placebo in Patients With Metastatic Chemotherapy-naive Pancreatic Adenocarcinoma.

Background: Imexon is a cyanoaziridine-derived iminopyrrolidone which has synergistic cytotoxicity with gemcitabine. A phase 1 study of the combination demonstrated good tolerance with encouraging clinical activity and thus we conducted this randomized phase II study. Materials and Methods: Patients with measurable, metastatic, treatment-naive pancreatic adenocarcinoma were randomized 1:1 to receive gemcitabine at 1000 mg/m2 days 1, 8, and 15 with either imexon, 875 mg/m2 or placebo days 1, 8, and 15 every 28 days. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and response rate. Results: A total of 142 patients were randomized, 72 to the imexon containing arm and 70 to the placebo arm. Patients in the imexon arm received an average of 3.6 cycles (range, 1 to 23) compared with 4.4 (range, 1 to 21) in the placebo arm. There was no increased rate of >=grade 3 toxicity in the imexon arm. Seven patients had objective responses in the imexon arm (13.7%), whereas 9 did in the placebo arm (17%). In the imexon arm, 23 patients had >=50% reduction in CA 19-9 from baseline (33%), whereas 22 did in the placebo arm (31.4%). The median progression-free survival was 2.8 months in the imexon arm (95% confidence interval [CI], 2.0-4.1 m) and 3.8 months in the placebo arm (95% CI, 2.2-4.7 m), P=0.504. The median overall survival time in the imexon arm was 5.2 months (95% CI, 4.2-6.7 m) as compared with 6.8 m (95% CI, 4.9-8.5 m) in the placebo arm, P=0.6822. Conclusions: The combination of imexon and gemcitabine does not result in improved outcome as initial therapy of metastatic pancreatic adenocarcinoma. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.

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SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma

BACKGROUND

Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma.

METHODS

Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%.

RESULTS

A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients.

CONCLUSIONS

Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity. Cancer 2015. © 2015 American Cancer Society.

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Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project

BACKGROUND

MYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA.

METHODS

Data from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patients with maximal differences in rates of MNA.

RESULTS

All clinical features (age ≥ 18 months, high ferritin levels, high lactate dehydrogenase [LDH] levels, International Neuroblastoma Staging System stage 4, and adrenal sites) and pathological/biological features (DNA index ≤ 1, high mitosis-karyorrhexis index [MKI], undifferentiated/poorly differentiated grade, unfavorable histology according to the International Neuroblastoma Pathology Classification, and segmental chromosomal aberrations [SCAs]) were significantly associated with MNA. LDH (odds ratio [OR], 8.4; P < .001) and chromosomal 1p loss of heterozygosity (OR, 19.8; P < .001) were the clinical and biological variables, respectively, most strongly associated with MNA. In logistic regression, all variables except chromosome 17q aberration and pooled SCAs were independently predictive of MNA. Recursive partitioning identified subgroups with disparate rates of MNA, including subgroups with 85.7% MNA (patients with high LDH levels who had poorly differentiated adrenal tumors with chromosome 1p deletion) and 0.6% MNA (localized tumors having hyperdiploidy and low MKIs and lacking chromosome 1p aberrations).

CONCLUSIONS

MNA is strongly associated with other clinical and biological variables in neuroblastoma. Recursive partitioning has identified subgroups of neuroblastoma patients with highly disparate rates of MNA. These findings can be used to inform investigations of molecular mechanisms of MNA. Cancer 2015. © 2015 American Cancer Society.

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Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS-activated tumors

BACKGROUND

The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents.

METHODS

This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)–mutated/amplified non–small cell lung cancer.

RESULTS

Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m² for paclitaxel on day 1, and 3 × 10¹⁰ 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m² for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months.

CONCLUSIONS

Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration. Cancer 2015. © 2015 American Cancer Society.

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Disparities in the use of screening magnetic resonance imaging of the breast in community practice by race, ethnicity, and socioeconomic status

BACKGROUND

Uptake of breast magnetic resonance imaging (MRI) coupled with breast cancer risk assessment offers the opportunity to tailor the benefits and harms of screening strategies for women with differing cancer risks. Despite the potential benefits, there is also concern for worsening population-based health disparities.

METHODS

Among 316,172 women aged 35 to 69 years from 5 Breast Cancer Surveillance Consortium registries (2007-2012), the authors examined 617,723 negative screening mammograms and 1047 screening MRIs. They examined the relative risks (RRs) of MRI use by women with a <20% lifetime breast cancer risk and RR in the absence of MRI use by women with a ≥20% lifetime risk.

RESULTS

Among women with a <20% lifetime risk of breast cancer, non-Hispanic white women were found to be 62% more likely than nonwhite women to undergo an MRI (95% confidence interval, 1.32-1.98). Of these women, those with an educational level of some college or technical school were 43% more likely and those who had at least a college degree were 132% more likely to receive an MRI compared with those with a high school education or less. Among women with a ≥20% lifetime risk, there was no statistically significant difference noted with regard to the use of screening MRI by race or ethnicity, but high-risk women with a high school education or less were less likely to undergo screening MRI than women who had graduated from college (RR, 0.40; 95% confidence interval, 0.25-0.63).

CONCLUSIONS

Uptake of screening MRI of the breast into clinical practice has the potential to worsen population-based health disparities. Policies beyond health insurance coverage should ensure that the use of this screening modality reflects evidence-based guidelines. Cancer 2015. © 2015 American Cancer Society.

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Wnt5a-Ror2 signaling in mesenchymal stem cells promotes proliferation of gastric cancer cells by activating CXCL16-CXCR6 axis

Summary

Wnt5a-Ror2 signaling has been shown to play important roles in promoting aggressiveness of various cancer cells in a cell-autonomous manner. However, little is known about its function in cancer-associated stromal cells, including mesenchymal stem cells (MSCs). Thus, we examined the role of Wnt5a-Ror2 signaling in bone marrow-derived MSCs in regulating proliferation of undifferentiated gastric cancer cells. Co-culture of a gastric cancer cell line, MKN45 cells, with MSCs either directly or indirectly promotes proliferation of MKN45 cells, and suppressed expression of Ror2 in MSCs prior to co-culture inhibits enhanced proliferation of MKN45 cells. In addition, conditioned media from MSCs, treated with control siRNA, but not siRNAs against Ror2, can enhance proliferation of MKN45 cells. Interestingly, it was found that expression of CXCL16 in MSCs is augmented by Wnt5a-Ror2 signaling, and that recombinant CXCL16 protein can enhance proliferation of MKN45 cells in the absence of MSCs. In fact, suppressed expression of CXCL16 in MSCs or an addition of a neutralizing antibody against CXCL16 fails to promote proliferation of MKN45 cells in either direct or indirect co-culture with MSCs. Importantly, we show that MKN45 cells express CXCR6, a receptor for CXCL16, and that suppressed expression of CXCR6 in MKN45 cells results in a failure of its enhanced proliferation in either direct or indirect co-culture with MSCs. These findings indicate that Wnt5a-Ror2 signaling enhances expression of CXCL16 in MSCs and as a result enhanced secretion of CXCL16 from MSCs might act on CXCR6 expressed on MKN45, leading to the promotion of its proliferation.

This article is protected by copyright. All rights reserved.

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FOXA1 expression affects to the proliferation activity of luminal breast cancer stem cell populations

Abstract

The expression of estrogen receptor (ER) is the key in most breast cancers (BC) and binding of ER to the genome correlates to Forkhead protein (FOXA1) expression. We herein assessed the correlation between the cancer stem cell (CSC) population and FOXA1 expression in luminal breast cancer (BC). We established luminal BC cells derived from metastatic pleural effusion and analyzed the potency of CSC and related factors with established luminal BC cell lines. We also confirmed that mammosphere cultures have an increased aldehyde dehydrogenase (ALDH)-positive population, which is one of the CSC markers, compared with adherent culture cells. Using a qPCR analysis, we found that mammosphere forming cells showed a higher expression of FOXA1 and stemness-related genes compared with adherent culture cells.

Furthermore, the growth activity and colony-forming activity of 4-hydroxytamoxifen (4-OHT)-treated BC cells were inhibited in a mammosphere assay. Interestingly, 4-OHT -resistant cells had significantly increased FOXA1 gene expression levels. Finally, we established short hairpin RNA of FOXA1 (shFOXA1) MCF-7 cells and investigated the relationship between self-renewal potential and FOXA1 expression. As a result, we found no significant difference in the number of mammospheres but decreased colony formation in shFOXA1 MCF-7 cells compared with control. These results suggest that the expression of FOXA1 appears to be involved in the proliferation of immature BC cells rather than the induction of stemness-related genes and self-renewal potency of CSCs.

This article is protected by copyright. All rights reserved.

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Clinical significance of accounting for tissue heterogeneity in permanent breast seeds implant brachytherapy planning

Publication date: Available online 23 December 2015
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Shahram Mashouf, Emmanuelle Fleury, Priscilla Lai, Tomas Merino, Eli Lechtman, Alex Kiss, Claire McCann, Jean-Philippe Pignol
PurposeThe Inhomogeneity Correction Factor (ICF) method provides heterogeneity correction for the fast calculation TG43 formalism in seeds brachytherapy. This study compared ICF corrected plans to their standard TG43 counterparts looking at their capacity to assess inadequate coverage and/or risk of any skin toxicities for patients who received Permanent Breast Seed Implant (PBSI).Methods and MaterialsThe 2 month post implant CT-scans and plans of 140 PBSI patients were used to calculate dose distributions using the TG-43U1 formalism and the ICF method. Multiple dose-volume histogram (DVH) parameters of clinical target volume (CTV) and skin were extracted and compared for both ICF and TG43 dose distributions. Short term (desquamation and erythema) and long term (telangiectasia) skin toxicity data were available on 125 and 110 of the patients, respectively, at the time of study. The predictive value of each DVH parameter of skin was evaluated using the area under the receiver operating characteristic (ROC) curve for each toxicity endpoint.ResultsThe DVH parameters of CTV calculated using the ICF method showed an overall decrease compared to TG43 while those of skin showed an increase confirming previously reported findings on the impact of heterogeneity with low energy sources. The ICF methodology enabled us to distinguish patients for whom the CTV V100 and V90 are up to 19% lower compared to TG43, which could present a risk of recurrence not detected when heterogeneity are not accounted for. The ICF method also led to an increase in the prediction of desquamation, erythema, and telangiectasia91% of skin DVH parameters studied.ConclusionsThe ICF methodology has the advantage to distinguish any inadequate dose coverage of CTV due to breast heterogeneity, which can be missed by TG43. The use of the ICF correction also led to an increase in prediction accuracy of skin toxicities in majority of cases.

Teaser

In this study we compared a tissue heterogeneity correction algorithm (ICF method) to the standard AAPM-TG43 protocol for a cohort of patients treated with permanent breast seed implants (PBSI). Using heterogeneity correction enabled distinguishing patients who received lower dose to the clinical target volume (CTV), who would otherwise go undetected using TG43. The use of the ICF correction also led to an increase in prediction accuracy of skin toxicities in the majority of the cases.


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Issue Information

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Psychosocial Palliative Care By William S. Breitbart and Yesne Alici. Oxford University Press, New York, 2014, 192 pages, ISBN: 9780199917402, Cost £32.99

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The willingness and actual situation of Chinese cancer patients and their family members participating in medical decision-making

Abstract

Objective

In China, not only patients and physicians are involved in medical decision-making (MDM) but also the patients' family members. The objective is to investigate the willingness and actual situation of cancer patients and their family members participating in the MDM process.

Methods

In this cross-sectional study, questionnaires were administered to 247 pairs of cancer inpatients and their relatives. Information regarding participants' willingness and actual experience during the decision-making process was documented. Eligible participants were cancer inpatients or their relatives, 18 years of age or older, and informed of the cancer diagnosis. All the patients should have received chemotherapy.

Results

The effective response rate was 72.9% (180/247). Over half of the patients (53.3%) and family members (57.8%) were willing to be part of the MDM process. In contrast, only 35.0% of patients and 46.1% of family members actually experienced this process (p = 0.001 and p = 0.011, respectively). Fewer family members (42.2%) than patients (53.3%) believed that patients should be involved in the MDM process (p < 0.001). Patients who were the head of their family (odds ratio 2.577, 95% CI 1.198–5.556, p = 0.015) experienced more involvement in MDM.

Conclusions

Although more than half of Chinese cancer patients and family members wanted to be part of MDM, the actual participation was below their expectation. Majority of family members do not want the patients to be involved in the process of MDM. Copyright © 2015 John Wiley & Sons, Ltd.

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Sleep disturbances and related factors among family caregivers of patients with advanced cancer

Abstract

Objective

Sleep disturbances among family caregivers (FCs) are common in advanced cancer. The comprehensive factors for sleep disturbances among the FCs of patients with cancer have not been investigated in Taiwan. The purposes of this study were to investigate the sleep disturbances among the FCs of patients with advanced cancer and to determine predictors of sleep disturbance.

Methods

A descriptive, cross-sectional study was conducted among 172 FCs. Data were collected using the Pittsburgh Sleep Quality Index and wrist actigraphy. A linear regression model was used to identify the predictive factors for sleep quality.

Results

Seventy-six percent of the FCs experienced some sleep disturbances. Female gender, more fatigue, greater depression, more caregiving burden, and spending over 16 h per day on caregiving tasks were risk factors for sleep disturbances in caregivers.

Conclusions

Sleep disturbances were common among the Taiwanese FCs of patients with advanced cancer. FCs with risk factors for sleep disturbances should be identified and provided assistance. Copyright © 2015 John Wiley & Sons, Ltd.

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National study of chronic disease self-management: 6-month and 12-month findings among cancer survivors and non-cancer survivors

Abstract

Objective

This study examined the applicability of the Stanford Chronic Disease Self-Management Program (CDSMP) for cancer survivors and compared outcomes among cancer survivors and participants with other chronic diseases (non-cancer survivors).

Methods

Participants were older adults (n = 1170) enrolled in the National Study of CDSMP. Detailed information about physical and psychosocial health status and health and healthcare behaviors was collected from participants (n = 116 cancer survivors and n = 1054 non-cancer survivors) via self-report before CDSMP participation and at 6-month and 12-month follow-ups. Linear and generalized linear mixed models were used to assess baseline-to-6-month and baseline-to-12-month changes.

Results

Among cancer survivors, general health, depression, and sleep significantly improved from baseline to 6 months. These significant changes were sustained at 12 months. Communication with physician, medication compliance, pain, days in poor physical health, days in poor mental health, and days kept from usual activities and physical activity also improved significantly from baseline to 12 months. Among non-cancer survivors, all outcomes except medication compliance and stress improved significantly from baseline to 6 months. At 12 months, medication compliance also improved significantly.

Conclusions

Findings suggest that participation in CDSMP, an evidence-based chronic disease self-management intervention not specifically tailored for cancer survivorship, may significantly improve physical and psychosocial health status and key health and healthcare behaviors among cancer survivors. Additional research is needed to elucidate cancer survivors' unique needs and examine the benefits of tailored versions of CDSMP. Nevertheless, CDSMP, available at scale nationally and internationally, is a promising intervention for cancer survivors and should be considered a valuable component of survivorship care. Copyright © 2015 John Wiley & Sons, Ltd.

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