Inhibition of PAK4 and NAMPT decreases RCC growth

Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the US and one of the relatively few whose incidence is increasing. Due to the near universal resistance which occurs with the use of current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies of this disease. Borrowing from studies on other malignancies, we have identified the PAK4 and NAD biosynthetic pathways as being essential for RCC growth. We now show, using the dual PAK4/NAMPT inhibitor KPT-9274, that interference with these signaling pathways results in reduction of G2/M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. Furthermore, NAPRT1 downregulation which we show occurs in all RCC cell lines tested makes this tumor highly dependent on NAMPT for its NAD requirements, such that inhibition of NAMPT by KPT-9274 leads to decreased survival of these rapidly proliferating cells. When KPT-9274 was administered in vivo to a 786-O (VHL-mut) human RCC xenograft model, there was dose-dependent inhibition of tumor growth with no apparent toxicity; KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 is being evaluated in a phase 1 human clinical trial in solid tumors and lymphomas which will allow this data to be rapidly translated into the clinic for the treatment of RCC.

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Plk1 and AR in HSP90-targeted therapy

Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer (PCa) when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) re-activation is responsible for the recurrence of PCa after ADT. Thus targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSPs) are chaperones that modify stability and activity of their client proteins. HSP90, a major player of the HSP family, regulates stabilities of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events. Further, HSP90 is overexpressed in different cancers, including PCa. Herein, we show that co-treatment of PCa with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that co-targeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that co-targeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC.

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{beta}-catenin targeting DsiRNAs

The Wnt/β-catenin pathway is among the most frequently altered signaling networks in human cancers. Despite decades of preclinical and clinical research, efficient therapeutic targeting of Wnt/β-catenin has been elusive. RNA interference (RNAi) technology silences genes at the mRNA level, and therefore can be applied to previously-undruggable targets. Lipid nanoparticles (LNPs) represent an elegant solution for delivery of RNAi-triggering oligonucleotides to disease-relevant tissues, but have been mostly restricted to applications in the liver. In this study, we systematically tuned the composition of a prototype LNP to enable tumor-selective delivery of a Dicer-substrate siRNA (DsiRNA) targeting CTNNB1, the gene encoding β-catenin. This formulation, termed EnCore-R, demonstrated pharmacodynamic activity in subcutaneous human tumor xenografts, orthotopic patient-derived xenograft (PDx) tumors, disseminated hematopoietic tumors, genetically induced primary liver tumors, metastatic colorectal tumors, murine metastatic melanoma. DsiRNA delivery was homogeneous in tumor sections, selective over normal liver and independent of apolipoprotein-E binding. Significant tumor growth inhibition was achieved in Wnt-dependent colorectal and hepatocellular carcinoma models, but not in Wnt-independent tumors. Finally, no evidence of accelerated blood clearance or sustained liver transaminase elevation was observed after repeated dosing in nonhuman primates. These data support further investigation to gain mechanistic insight, optimize dose regimens and identify efficacious combinations with standard-of-care therapeutics.

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Relationship between self-reported and objectively measured physical activity and subjective memory impairment in breast cancer survivors: role of self-efficacy, fatigue and distress

Abstract

Purpose

Many breast cancer survivors report cancer and cancer treatment-associated cognitive change. However, very little is known about the relationship between physical activity and subjective memory impairment (SMI) in this population. The purpose of this study is to examine the relationship between physical activity and SMI and longitudinally test a model examining the role of self-efficacy, fatigue and distress as potential mediators.

Methods

Post-treatment breast cancer survivors (N = 1477) completed measures of physical activity, self-efficacy, distress (depression, concerns about recurrence, perceived stress, anxiety), fatigue and SMI at baseline and 6-month follow-up. A subsample (n = 362) was randomly selected to wear an accelerometer. It was hypothesized that physical activity indirectly influences SMI via exercise self-efficacy, distress and fatigue. Relationships were examined using panel analysis within a covariance modeling framework.

Results

The hypothesized model provided a good fit in the full sample (χ² = 1462.5, df = 469, p = <0.001; CFI = 0.96; SRMR = 0.04) and the accelerometer subsample (χ2 = 961.8, df = 535, p = <0.001, CFI = 0.94, SRMR = 0.05) indicating increased physical activity is indirectly associated with reduction in SMI across time, via increased exercise self-efficacy and reduced distress and fatigue.

Conclusions

Higher levels of physical activity, lower levels of fatigue and distress and higher exercise self-efficacy may play an important role in understanding SMI in breast cancer survivors across time. Future research is warranted to replicate and explore these relationships further. Copyright © 2016 John Wiley & Sons, Ltd.

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Distribution and Patterns of Industry-Related Payments to Oncologists in 2014

Background: Industry-physician collaboration is critical for anticancer therapeutic development, but financial relationships introduce conflicts of interest. We examined the specialty variation and context of physician payments and ownership interest among oncologists.

Methods: We performed a population-based multivariable analysis of 2014 Open Payments reports of industry payments to US physicians matched to physician and practice data, including sex, specialty, practice location, and sole proprietor status. Payment data were aggregated per physician and compared by specialty (medical, radiation, surgical, and nononcology), and practice location linked with spending level (low, average, and high). Primary outcomes included likelihood, mean annual amount, and number of general payments. Secondary outcomes included likelihood of holding ownership interests and receipt of royalty/license payments. Estimates for each outcome were determined using multivariable models, including logistic regression for likelihood and linear regression with gamma distribution and log-link for value, adjusted for physician specialty, sex, sole proprietor status, and practice spending. All statistical tests were two-sided.

Results: In 2014, there were 883 438 physicians, including 22 712 oncologists, licensed to practice in the United States. Among oncology specialties, 52.4% to 63.0% of physicians received a general payment in 2014, totaling $76 million, $4 million, and $5 million to medical, radiation, and surgical oncology, respectively. The median annual per-physician payment to medical oncologists was $632 (IQR = 136–2500), compared with $124 (IQR = 39–323) in radiation oncology and $250 (IQR = 84–1369) in surgical oncology. After controlling for physician and practice characteristics, oncologists were 1.09 to 1.75 times as likely to receive a general payment compared with nononcologists (overall P < .001). There was a 67.6% difference (95% confidence interval [CI] = 63.6 to 71.5, P < .001) in the mean annual value of payments between medical oncology and nononcology specialties (vs –92.7%, 95%CI = –100.2 to –85.0, P < .001] for radiation oncology). Medical and radiation oncologists were more likely to hold ownership interest (adjusted OR = 3.72, 95% CI = 3.22 to 4.27, and 2.27, 95% CI = 1.65 to 3.03, respectively, P < .001 both comparisons).

Conclusions: In 2014, industry-oncologist financial relationships were common, and their impact on oncology practice should be further explored.

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RE: Regorafenib Also Can Cause Osteonecrosis of the Jaw

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Response

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Primary Desmoid-Type Fibromatosis of the Mesentery: Report of an Unusual Tumor Localization

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Preclinical study of CE7-CAR T cell therapy in neuroblastoma

Purpose: The identification and vetting of cell surface tumor restricted epitopes for chimeric antigen receptor (CAR) redirected T cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation dependent tumor-specific epitope recognized by the CE7 monoclonal antibody. Experimental Design: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a pre-clinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed. Results: CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 1x108/kg CE7-CAR+ CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4+ and CD8+ CE7-CAR T cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T cell products demonstrated in vitro and in vivo anti-tumor activity. Conclusion: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T cell target for neuroblastoma immunotherapy.

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Oncolytic virus therapy in conjunction with bortezomib

Background: Both the proteasome inhibitor bortezomib and an oncolytic herpes simplex virus-1 (oHSV) expressing GMCSF are currently FDA-approved. While proteasome blockade can increase oHSV replication, immunological consequences and consequent immunotherapy potential are unknown. In this study, we investigated the impact of bortezomib combined with oHSV on tumor cell death and sensitivity to Natural Killier (NK) cell immunotherapy. Experimental Design: Western blot, flow cytometry, and caspase 3/7 activity assays were used to evaluate the induction of apoptosis/autophagy and/or necroptotic cell death. Cellular and mitochondrial reactive oxygen species (ROS) production was measured utilizing CellROX{trade mark, serif} and MitoSOX. Inhibitors/shRNA targeting ROS, JNK and RIP1 kinase (RIPK1) were utilized to investigate the mechanism of cell killing. The synergistic interaction between oHSV and bortezomib was calculated using a Chou-Talalay analysis. NK cells isolated from normal human blood were co-cultured with tumor cells to evaluate cellular interactions. Q-PCR, ELISA, and FACS analysis were used to evaluate NK cell activation. Intracranial tumor xenografts were utilized to evaluate anti-tumor efficacy. Results: Combination treatment with bortezomib and oHSV induced necroptotic cell death and increased the production of mitochondrial ROS and JNK phosphorylation. Inhibitors/shRNA of RIPK1 and JNK rescued synergistic cell killing. Combination treatment also significantly enhanced NK cell activation and adjuvant NK cell therapy of mice treated with bortezomib and oHSV improved anti-tumor efficacy. Conclusions: This study provides a significant rationale for triple combination therapy with bortezomib, oHSV, and NK cells to improve efficacy, in glioblastoma patients.

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Mutational Landscape and Immunity in Cancer

Immunotherapy is currently transforming cancer treatment. Notably, immune checkpoint blockers (ICB) have shown unprecedented therapeutic successes in numerous tumor types, including cancers that were traditionally considered as non-immunogenic. However, a significant proportion of patients do not respond to these therapies. Thus, early selection of the most sensitive patients is key, and the development of predictive companion biomarkers constitutes one of the biggest challenges of ICB development. Recent publications have suggested that the tumor genomic landscape, mutational load, and tumor-specific neoantigens, are potential determinants of the response to ICB and can influence patients' outcome upon immunotherapy. Further, defects in the DNA repair machinery have consistently been associated with improved survival and durable clinical benefit from ICB. Thus, closely reflecting the DNA damage repair capacity of tumor cells and their intrinsic genomic instability, the mutational load and its associated tumor-specific neoantigens appear as key predictive paths to anticipate potential clinical benefits of ICB. In the era of next generation sequencing, while more and more patients are getting the full molecular portrait of their tumor, it is crucial to optimally exploit sequencing data for the benefit of patients. Therefore, sequencing technologies, analyses tools and relevant criteria for mutational load and neoantigens prediction should be homogenized and combined in more integrative pipelines, to fully optimize the measurement of such parameters, so that these biomarkers can ultimately reach the analytical validity and reproducibility required for a clinical implementation.

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Quadruple-negative GIST is a sentinel for NF1 syndrome

Purpose: The majority of Gastrointestinal Stromal Tumors (GISTs) are driven by KIT, PDGFRA or, less commonly, BRAF mutations, and SDH gene inactivation is involved in a limited fraction of gastric lesions. However, about 10% of GISTs are devoid of any of such alterations and are poorly responsive to standard treatments. This study aims to shed light on the molecular drivers of quadruple-negative GISTs. Experimental Design: Twenty-two sporadic quadruple-negative GISTs with no prior association with Neurofibromatosis Type 1 syndrome were molecularly profiled for a panel of genes belonging to tyrosine kinase pathways or previously implicated in GISTs. For comparison purposes, 24 GISTs carrying KIT, PDGFRA, or SDH gene mutations were also analyzed. Molecular findings were correlated to clinicopathological features. Results: Most quadruple-negative GISTs featured intestinal localization, with a female predilection. About 60% (13/22) of quadruple-negative tumors carried NF1 pathogenic mutations, often associated with biallelic inactivation. The analysis of normal tissues, available in 11 cases, indicated the constitutional nature of the NF1 mutation in 7/11 cases, unveiling an unrecognized Neurofibromatosis Type 1 syndromic condition. Multifocality and a multinodular pattern of growth were common findings in NF1-mutated quadruple-negative GISTs. Conclusions: NF1 gene mutations are frequent in quadruple-negative GISTs and are often constitutional, indicating that a significant fraction of patients with apparently sporadic quadruple-negative GISTs are affected by unrecognized Neurofibromatosis Type 1 syndrome. Hence, a diagnosis of quadruple-negative GIST, especially if multifocal or with a multinodular growth pattern and a non-gastric location, should alert the clinician to a possible Neurofibromatosis Type 1 syndromic condition.

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Preclinical PET imaging of EGFR levels: pairing a targeting with a non-targeting Sel-tagged Affibody-based tracer to estimate the specific uptake

Abstract

Background

Though overexpression of epidermal growth factor receptor (EGFR) in several forms of cancer is considered to be an important prognostic biomarker related to poor prognosis, clear correlations between biomarker assays and patient management have been difficult to establish. Here, we utilize a targeting directly followed by a non-targeting tracer-based positron emission tomography (PET) method to examine some of the aspects of determining specific EGFR binding in tumors.

Methods

The EGFR-binding Affibody molecule Z_EGFR:2377 and its size-matched non-binding control Z_Taq:3638 were recombinantly fused with a C-terminal selenocysteine-containing Sel-tag (Z_EGFR:2377-ST and Z_Taq:3638-ST). The proteins were site-specifically labeled with DyLight488 for flow cytometry and ex vivo tissue analyses or with ¹¹C for in vivo PET studies. Kinetic scans with the ¹¹C-labeled proteins were performed in healthy mice and in mice bearing xenografts from human FaDu (squamous cell carcinoma) and A431 (epidermoid carcinoma) cell lines. Changes in tracer uptake in A431 xenografts over time were also monitored, followed by ex vivo proximity ligation assays (PLA) of EGFR expressions.

Results

Flow cytometry and ex vivo tissue analyses confirmed EGFR targeting by Z_EGFR:2377-ST-DyLight488. [Methyl-¹¹C]-labeled Z_EGFR:2377-ST-CH₃ and Z_Taq:3638-ST-CH₃ showed similar distributions in vivo, except for notably higher concentrations of the former in particularly the liver and the blood. [Methyl-¹¹C]-Z_EGFR:2377-ST-CH₃ successfully visualized FaDu and A431 xenografts with moderate and high EGFR expression levels, respectively. However, in FaDu tumors, the non-specific uptake was large and sometimes equally large, illustrating the importance of proper controls. In the A431 group observed longitudinally, non-specific uptake remained at same level over the observation period. Specific uptake increased with tumor size, but changes varied widely over time in individual tumors. Total (membranous and cytoplasmic) EGFR in excised sections increased with tumor growth. There was no positive correlation between total EGFR and specific tracer uptake, which, since Z_EGFR:2377 binds extracellularly and is slowly internalized, indicates a discordance between available membranous and total EGFR expression levels.

Conclusions

Same-day in vivo dual tracer imaging enabled by the Sel-tag technology and ¹¹C-labeling provides a method to non-invasively monitor membrane-localized EGFR as well as factors affecting non-specific uptake of the PET ligand.

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Eribulin-induced liver dysfunction as a prognostic indicator of survival of metastatic breast cancer patients: a retrospective study

Abstract

Background

Eribulin is a non-taxane, microtubule dynamics inhibitor that increases survival of patients with metastatic breast cancer. Although eribulin is well tolerated in patients with heavily pretreated disease, eribulin-induced liver dysfunction (EILD) can occur, resulting in treatment modification and subsequent poor disease control. We aimed to clarify the effect of EILD on patient survival.

Methods

The medical records of 157 metastatic breast cancer patients treated with eribulin between July 2011 and November 2013 at Cancer Institute Hospital were retrospectively analyzed. EILD was defined as 1) an increase in alanine aminotransferase or aspartate aminotransferase levels >3 times the upper limit of normal, and/or 2) initiation of a liver-supporting oral drug therapy such as ursodeoxycholic acid or glycyron. Fatty liver was defined as a decrease in the liver-to-spleen attenuation ratio to <0.9 on a computed tomography scan.

Results

EILD occurred in 42 patients, including one patient for whom eribulin treatment was discontinued due to severe EILD. The patients who developed EILD had significantly higher body mass indices (BMIs) than those who did not develop EILD (24.5 vs. 21.5, respectively; P < 0.0001), with no difference in the dose intensity of eribulin between the two groups (P = 0.76). Interestingly, the patients with EILD exhibited significantly longer progression-free survival (PFS) and overall survival (OS) than those without EILD (P = 0.010 and P = 0.032, respectively). Similarly, among 80 patients without liver metastasis, 19 with EILD exhibited significantly longer PFS and OS than the others (P = 0.0012 and P = 0.044, respectively), and EILD was an independent prognostic factor of PFS (P = 0.0079) in multivariate analysis. During eribulin treatment, 18 patients developed fatty liver, 11 of whom developed EILD, with a median BMI of 26.7.

Conclusions

Although EILD and fatty liver occurred at a relatively high frequency in our study, most of the patients did not experience severe adverse effects. Surprisingly, the development of EILD was positively associated with patient survival, especially in patients without liver metastases. EILD may be a clinically useful predictive biomarker of survival, but further studies are needed to confirm these findings in another cohort of patients.

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Predictive factors for a long-term response duration in non-squamous cell lung cancer patients treated with pemetrexed

Abstract

Background

Pemetrexed is widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSCLC). However, factors that can predict the benefits of pemetrexed therapy have not yet been defined.

Methods

We compared the clinical and molecule pathological characteristics of good and poor responders among a cohort of 1,848 non-squamous NSCLC patients who had received at least two cycles of pemetrexed therapy between November 2006 and February 2015. Among these cases, 92 good responders who were the top 5 % in terms of progression-free survival (PFS) and 222 poor responders who had progressive disease after only 2 cycles of therapy were selected for the analysis.

Results

The median PFS of the good responders was 29.9 months (range; 20.9–90.0) and the median number of cycle was 37 (range; 18–129). Although 53.5 % of patients showed stable disease (SD), this response was sustained (median PFS in SD, 29.6 months). A never-smoking status was related to better survival outcome, whereas EGFR mutation, two or more metastatic sites, and intra-abdominal metastasis were each associated with a poor PFS. ALK translocation showed a tendency for a positive impact on response to pemetrexed, whereas metastatic lesion to liver, adrenal gland or bone showed a tendency for a negative impact despite not reaching our threshold for statistical significance.

Conclusions

Predictive factors, such as smoking status, the status of genetic alteration and tumor burden, should be considered when administering pemetrexed therapy for non-squamous NSCLC.

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Clinicopathological and prognostic significance of GPX2 protein expression in esophageal squamous cell carcinoma

Abstract

Background

Chaoshan region, a littoral area of Guangdong province in southern China, has a high incidence of esophageal squamous cell carcinoma (ESCC). At present, the prognosis of ESCC is still very poor, therefore, there is urgent need to seek valuable molecular biomarker for prognostic evaluation to guide clinical treatment. GPX2, a selenoprotein, was exclusively expressed in gastrointestinal tract and has an anti-oxidative damage and anti-tumour effect in the progress of tumourigenesis.

Methods

We collected 161 ESCC patients samples, among which 83 patients were followed up. We employed immunochemistry analysis, western blotting and quantitative real-time PCR for measuring the expression of GPX2 within ESCC samples. We analysed the relationship between the expression of GPX2 and clinicopathological parameters of 161 patients with ESCC by Chi-square or Fisher's exact test. The survival analysis of GPX2 expression within ESCC tissues was evaluated by the Kaplan-Meier method and Cox-regression.

Results

A significant higher expression level of GPX2 was detected in tumour tissues compared to that in non-tumour tissues (P < 0.001). Moreover, GPX2 expression has statistically significant difference in the tumour histological grade of ESCC (P < 0.001), while there was no statistically significant difference in age, sex, tumour size, tumour location, gross morphology and clinical TNM stages (P > 0.05). Meanwhile, the expression of GPX2 protein was obviously down-regulated within poorly differentiated ESCC. Last, survival analysis revealed that tumour histological grade and clinical TNM stages, both of the clinical pathological parameters of ESCC, were associated with the prognosis of patients with ESCC (respectively, P = 0.009, HR (95 % CI) = 1.885 (1.212 ~ 2.932); P = 0.007, HR (95 % CI) = 2.046 (1.318 ~ 3.177)). More importantly, loss expression of GPX2 protein predicted poor prognosis in patients with ESCC (P < 0.001, HR (95 % CI) = 5.700 (2.337 ~ 13.907)).

Conclusions

Collectively, these results suggested that the expression of GPX2 was significantly up-regulated within ESCC tumour tissues. GPX2 might be an important predictor for the prognosis of ESCC and a potential target for intervention and treatment of ESCC.

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GSK-3 directly regulates phospho-4EBP1 in renal cell carcinoma cell-line: an intrinsic subcellular mechanism for resistance to mTORC1 inhibition

Abstract

Background

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin 1 (mTORC1) signaling pathway is aberrantly activated in renal cell carcinoma (RCC). We previously demonstrated glycogen synthase kinase-3β (GSK-3β) positively regulated RCC proliferation. The aim of this study was to evaluate the role of GSK-3 in the PI3K/Akt/mTORC1 pathway and regulation of the downstream substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), ribosomal protein S6 kinase (S6K), and ribosomal protein S6 (S6RP).

Methods

We used human RCC cell lines (ACHN, Caki1, and A498) and, as normal controls, human renal proximal tubular epithelial cell (HRPTEpC) and non-tumorous kidney tissues that were obtained surgically for treatment of RCC patients. Rapamycin-resistant ACHN (ACHN/RR) cells were generated with chronic exposure of ACHN to rapamycin ranging from 1nM finally to 1 μM. Cell viability, cell cycling and direct interaction between GSK-3β and 4EBP1 were evaluated with MTS assay, flowcytometry and in vitro kinase assay with recombinant GSK-3β and 4EBP1products, respectively. Protein expression and phosphorylation of molecules associated with the PI3K/Akt/mTORC1 pathway were examined by immunoblotting. Effects of drug combination were determined as the combination index with CompuSyn software.

Results

Overexpression and phosphorylation of 4EBP1 and S6RP together with GSK-3 activation were observed in RCC cell lines, but not in human normal kidney cells and tissues. Cell proliferation, p4EBP1 and pS6RP were strongly suppressed by GSK-3 inhibition. Rapamycin and LY294002 sufficiently decreased pS6RP, but only moderately p4EBP1. In vitro kinase assays showed that recombinant GSK-3β phosphorylated recombinant 4EBP1, and the effect was blocked by GSK-3 inhibitors. Different from rapamycin, AR- A014418 remarkably inhibited cell proliferation, and rapidly suppressed p4EBP1 and pS6RP in ACHN and ACHN/RR (in 30 min to 1 h). AR- A014418 and rapamycin combination showed additivity at lower concentrations, but antagonism at higher concentrations.

Conclusions

GSK-3β could directly phosphorylate 4EBP1 and activate the mTORC1 downstream signaling cascades to enhance protein biosynthesis and cell proliferation in RCC cell lines independent of rapamycin sensitivity. The direct GSK-3β/4EBP1 pathway might be an important subcellular mechanism as an inherent equipment for RCC cells to acquire clinical chemoresistance to mTORC1 inhibitors.

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Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway

Abstract

Background

The long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) plays a crucial role in cancer progression, which is regulated by the interferon regulatory factor-1 (IRF1) and up-streaming Akt activation. The present study evaluated the chemopreventive effects of delphinidin-3-glucoside (Dp), a major anthocyanin present in pigmented fruits and vegetables, on breast carcinogenesis, and investigate the role of the Akt/HOTAIR signaling pathway.

Methods

Human breast epithelial cells MCF10A were treated with carcinogens (NNK and B[a]P) or co-treated with carcinogens plus Dp for 30 days. Then, the cancer-associated properties of the treated cells were evaluated to assess the carcinogenesis and the effects of Dp. HOTAIR levels were detected by qRT-PCR. The proteins expression was measured by western blots, immunofluorescence and immunohistochemistry. Xenografted tumors were made by implanting breast cancer cells MDA-MB-231-Luc-GFP in athymic mice. ChIP-qPCR analysis was used to detect the IRF1 binding to the HOTAIR promoter.

Results

Carcinogens treatment induces apparent carcinogenic transformation in MCF10A cells including reduced dependence on growth factors, anchorage-independent cell growth and aberrant wound-healing ability, which is effectively suppressed by Dp co-treatment. The level of HOTAIR significantly increases in a time-dependent manner during chronic breast carcinogenesis. Dp treatment down-regulates HOTAIR expression in breast carcinogenesis and breast cancer cells. Furthermore, Dp administration inhibits the growth of xenografted breast tumors in athymic mice, and decreases HOTAIR in vivo. Further studies showed that Dp represses Akt activation, promotes IRF1 expression and increases IRF1 binding to the HOTAIR promoter. Silence of IRF1 expression via transfecting cells with IRF1 siRNAs significantly reduced the effects of Dp on HOTAIR, resulting in decreased cytotoxic effects of Dp on breast cancer cells.

Conclusions

These data suggest the effective chemopreventive effect of Dp on breast carcinogenesis, in which down-regulation of HOTAIR plays a critical role.

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Survival, safety, and prognostic factors for outcome with Regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBACCA) nested within a compassionate use program

Abstract

Background

Randomized trials have shown a survival benefit for regorafenib over placebo in patients with metastatic colorectal cancer (mCRC) that progressed after standard therapies. We evaluated survival and safety outcomes in patients treated with regorafenib in a real-life setting.

Methods

REBECCA is a cohort study nested within a compassionate use program designed to evaluate survival, safety, and potential prognostic factors for outcome associated with regorafenib in patients with mCRC refractory to standard therapies. Treatment effects according to various patient and tumour characteristics were evaluated using univariate and multivariate Cox proportional hazards regression models.

Results

Of 1178 patients in the compassionate use program, 654 were in the full analysis set. Median follow-up was 16.5 months. Median survival was 5.6 months. The 12-month survival rate was 22 %. Survival was independently and unfavourably affected by the following variables: poor performance status, short time from initial diagnosis of metastases to the start of regorafenib, low initial regorafenib dose, >3 metastatic sites, presence of liver metastases, and KRAS mutations. We identified prognostic groups of patients with low, intermediate, and high risk of death, with a median survival of 9.2, 5.2, and 2.5 months, respectively. Five-hundred-twenty-four patients (80 %) experienced at least one regorafenib-related adverse event, most commonly, fatigue, hand-foot skin reaction, diarrhea, anorexia, arterial hypertension, and mucositis.

Conclusion

The safety and efficacy profile of regorafenib in REBECCA are similar to those in randomized trials. Our prognostic model identified subgroups of mCRC patients who derived a minimal and maximum benefit from regorafenib.

Trial registration

Clinicaltrials.gov NCT02310477.

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Fluorescent imaging of superficial head and neck squamous cell carcinoma using a γ-glutamyltranspeptidase-activated targeting agent: a pilot study

Abstract

Background

Detecting superficial head and neck squamous cell carcinoma (HNSCC) by endoscopy is challenging because of limited morphological hallmarks, and iodine cannot be applied to head and neck lesions due to severe mucosal irritation. γ-glutamyltranspeptidase (GGT), a cell surface enzyme, is overexpressed in several cancers, and it has been reported that γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent targeting agent which can be enzymatically activated and becomes fluorescent after cleavage of a GGT-specific sequence, can be activated within a few minutes after application to animal models. We investigated whether early HNSCC can be detected by applying gGlu-HMRG to clinical samples.

Methods

gGlu-HMRG was applied to four HNSCC cell lines, and fluorescence was observed by fluorescence microscopy and flow cytometry. Immunohistological examination was performed in three recent cases of endoscopic submucosal dissection (ESD) to investigate GGT expression. Fluorescence imaging with gGlu-HMRG in eight clinical samples resected by ESD or surgery was performed, and fluorescence intensity of tumor and normal mucosa regions of interest (ROI) was prospectively measured.

Results

All four gGlu-HMRG-applied cell lines emitted green fluorescence. Immunohistological examination demonstrated that GGT was highly expressed in HNSCC of the recent three ESD cases but barely in the normal mucosa. Fluorescence imaging showed that iodine-voiding lesions became fluorescent within a few minutes after application of gGlu-HMRG in all eight resected tumors. Tumor ROI fluorescence intensity was significantly higher than in the normal mucosa five minutes after gGlu-HMRG application.

Conclusions

Fluorescence imaging with gGlu-HMRG would be useful for early detection of HNSCC.

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Tumor-suppressive effects of atelocollagen-conjugated hsa-miR-520d-5p on un-differentiated cancer cells in a mouse xenograft model

Abstract

Background

We previously demonstrated that hsa-miR-520d-5p can convert cancer cells into induced pluripotent stem cells (iPSCs) or mesenchymal stem cells (MSCs) via a demethylation process and p53 upregulation in vivo. Additionally, we have reported the non-tumorigenic effect of miR-520d-5p on normal human cells, including fibroblasts.

Methods

We used atelocollagen-conjugated miR-520d-5p (520d/atelocollagen) to confirm the possibility of a therapeutic effect on cancer cells. We traced the size and signal intensity of GFP-expressing tumors in mice each week, beginning 4 weeks after subcutaneous inoculation.

Results

520d/atelocollagen treatment suppressed tumor growth by greater than 80 % each week relative to controls and resulted in an approximately 30 % disappearance of tumors. In mice whose tumors disappeared, the existence of human genomic material at the injection site was examined by quantitative Alu-PCR, and we confirmed the co-existence of both species-derived cells. In every site where a tumor disappeared in immunodeficient mice, GFP protein was expressed in the connective tissues, and approximately 0.1 % of the extracted DNA contained human genomic material. We could not identify any adverse effects in vivo.

Conclusions

This is the first report to confirm an inhibitory effect of 520d/atelocollagen on cancer cells in vivo. The development of optimized modifications of this carrier is expected to enhance the efficiency of entry into tumor cells and the induction of its inhibitory effect.

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ColoNav: patient navigation for colorectal cancer screening in deprived areas – Study protocol

Abstract

Background

The mass colorectal cancer screening program was implemented in 2008 in France, targeting 16 million French people aged between 50 and 74. The current adhesion is insufficient and the participation rate is even lower among the underserved population, increasing health inequalities within our health care system. Patient Navigation programs have proved their efficiency to promote the access to cancer screening and diagnosis.

Methods/Design

The purpose of the study is to assess the implementation of a patient navigation intervention that has been described in another cultural environment and another health care system. The main objective of the program is to increase the colorectal cancer screening participation rate among the deprived population through the intervention of a navigator to promote the Fecal Occult Blood Test (FOBT) and complementary exams.

We performed a multisite cluster randomized controlled trial, with three groups (one experimental group and two control groups) for 18 months.

Discussion

The study attempts to give a better understanding of the adhesion barriers to colorectal cancer screening among underserved populations. If this project is cost-effective, it could create a dynamic based on peer approaches that could be developed for other cancer screening programs and other chronic diseases.

Trial registration

NCT02369757

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Increased neutrophil-to-lymphocyte ratio is associated with disease-specific mortality in patients with penile cancer

Abstract

Background

The neutrophil-to-lymphocyte ratio (NLR), a simple marker of the systemic inflammatory response, has been demonstrated to correlate with patient outcomes for various solid malignancies. We investigated the utility of the pretreatment NLR as a prognosticator in patients who presented with penile cancer.

Methods

A total of 41 patients who underwent complete blood count with differential and subsequent radical penectomy from 1988 to 2014 were analyzed. We assessed the correlation between the NLR and the prognosis of penile cancer.

Results

The median and mean (± SD) NLRs in 41 penile cancer patients were 3.42 and 5.03 ± 4.99, respectively. Based on the area under receiver operator characteristic curve, the cut-off value of NLR was determined to be 2.82. Patients with a high NLR (≥2.82) showed a significantly poorer cancer-specific survival (p = 0.023) than those with a low NLR.

Conclusions

The pretreatment NLR may function as a biomarker that precisely predicts the prognosis in patients with penile cancer.

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A cost effective analysis of fixed-dose combination of dutasteride and tamsulosin compared with dutasteride monotherapy for benign prostatic hyperplasia in Nigeria: a middle income perspective; using an interactive Markov model

Abstract

Background

The number of Nigerian men presenting with benign prostatic hyperplasia is on the rise because of increase awareness about the ailment. With the renewed effort by the national health insurance scheme to cover the informal sector, it becomes imperative to determine the cost implication for managing Benign Prostatic Hyperplasia (BPH) and the cost effective drug combination to be adopted. The objective of this study is to estimate cost effective analysis (CEA) of fixed -dose combination of dutasteride and tamsulosin compared with dutasteride monotherapy from the health service provider perspective design.

Methods

An interactive Markov's model was used to generate incremental cost per QALY and incremental cost per life years gained. 2.9 million Men who were 50 years of age were fed into the model. The outcome measures included: costs of drug treatment, consultation, acute urinary retention (AUR), transurethral resection of prostate (TURP), hospitalisation post TURP, and quality adjusted life years (QALYs), incremental cost per life years gained, and incremental cost per QALY gained.

Results

Fixed-dose combination of dutasteride and tamsulosin (FDCT) produced an Incremental cost-effectiveness ratios of US$1481.92 per Quality adjusted for life-years saved.

Conclusion

Universal FDCT provision for Nigeria has major economic implications. This study in the context of its limitations has demonstrated the cost effectiveness of FDCT for the long term treatment of patients with moderate to severe BPH from the perspective of a developing country. Currently, there are few studies available to give economic data evidence to policy makers in Nigeria which is applicable to developing countries with similar economies. As such, the findings in this study will be relevant to policy makers in these countries.

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Interleukin-22 is elevated in lavage from patients with lung cancer and other pulmonary diseases

Abstract

Background

Interleukin-22 (IL-22) is involved in lung diseases such as pneumonia, asthma and lung cancer. Lavage mirrors the local environment, and may provide insights into the presence and role of IL-22 in patients.

Methods

Bronchoscopic lavage (BL) samples (n = 195, including bronchoalveolar lavage and bronchial washings) were analysed for IL-22 using an enzyme-linked immunosorbent assay. Clinical characteristics and parameters from lavage and serum were correlated with lavage IL-22 concentrations.

Results

IL-22 was higher in lavage from patients with lung disease than in controls (38.0 vs 15.3 pg/ml, p < 0.001). Patients with pneumonia and lung cancer had the highest concentrations (48.9 and 33.0 pg/ml, p = 0.009 and p < 0.001, respectively). IL-22 concentration did not correlate with systemic inflammation. IL-22 concentrations did not relate to any of the analysed cell types in BL indicating a potential mixed contribution of different cell populations to IL-22 production.

Conclusions

Lavage IL-22 concentrations are high in patients with lung cancer but do not correlate with systemic inflammation, thus suggesting that lavage IL-22 may be related to the underlying malignancy. Our results suggest that lavage may represent a distinct compartment where the role of IL-22 in thoracic malignancies can be studied.

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Chemotherapy versus radiotherapy for FIGO stages IB1 and IIA1 cervical carcinoma patients with postoperative isolated deep stromal invasion: a retrospective study

Abstract

Background

The adjuvant treatment for patients with isolated stromal invasion after radical hysterectomy and pelvic lymph node dissection (PLND) in FIGO stage IB1 and IIA1 cervical carcinoma has not been established. This study assessed the survival outcomes and recurrent patterns in this particular group of patients treated with chemotherapy or radiation-based adjuvant therapy.

Methods

The records 133 IB1 and IIA1 postoperative cervical carcinoma patients with histopathology-confirmed isolated deep stromal invasion (DSI) without any other unfavorable pathological finding between June 2010 and March 2013 were analyzed. Sixty-five patients received postoperative adjuvant four to six cycles of cisplatin-based chemotherapy (CT group) and Sixty-eight received postoperative received postoperative adjuvant radiotherapy (RT group). Treatment-related toxicities were evaluated and disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier estimates and statistical significance was determined using the log-rank test.

Results

With a median follow-up of 33.7 months (range 10–62 months), RT group had a significantly improved in DFS rate (P = 0.044), but there was no significant difference in overall survival (P = 0.437). Upon further analysis, patients with outer 1/3 to full-thickness invasion in chemotherapy group exhibited significantly higher recurrence rates compared to the radiotherapy group. Leukocytopenia, nausea and vomiting were the most frequent short-term complications of chemotherapy, whereas colitis/proctitis and cystitis were more frequent in the radiotherapy group (P = 0.000 respectively). No significant differences were found regards to other acute toxicities, including hemoglobin, platelets and ALT/AST, colitis/proctitis, cystitis and dermatitis (P = 0.000 respectively). Fewer late severe side effects in the chemotherapy group were observed compared with the radiation group and significant differences were found at colitis/proctitis, cystitis and dermatitis (P = 0.000 respectively).

Conclusion

Compared to chemotherapy alone, postoperative RT to FIGO stages IB1 and IIA1 cervical carcinoma patients with isolated DSI can reduce risk of recurrence and with acceptable morbidity.

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Prognostic and predictive significance of tumor length in patients with esophageal squamous cell carcinoma undergoing radical resection

Abstract

Background

The objective of this study was to investigate the prognostic and predictive significance of tumor length in patients with esophageal squamous cell carcinoma undergoing radical resection.

Methods

Tumor length and other clinicopathological variables were retrospectively evaluated in 1435 patients with squamous cell carcinoma treated with radical resection between 2003 and 2010. Tumor length was analyzed as categorical and continuous variable. Associations with overall survival were assessed with Cox proportional hazards models. Model-based nomograms were constructed. Predictive accuracy was measured with C-index. Decision curve analysis was used to evaluate clinical usefulness of prediction models.

Results

Both categorically and continuously coded tumor length were independent prognostic factors in multivariable analysis. Adding categorically and continuously coded tumor length to TNM staging model increased predictive accuracy by 0.2 and 0.4 % respectively. Decision curve analysis revealed that the models built by the addition of categorically or continuously coded tumor length did not perform better than TNM staging model.

Conclusions

Tumor length is an independent prognostic factor in patients with esophageal squamous cell carcinoma treated with radical resection. It increases predictive accuracy of TNM staging system for overall survival in these patients. But it does not increase clinical usefulness of TNM staging system as a prediction model.

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INFα-2b inhibitory effects on CD4 + CD25 + FOXP3 + regulatory T cells in the tumor microenvironment of C57BL/6 J mice with melanoma xenografts

Abstract

Background

Regulatory T cells (Treg_s), particularly the CD4⁺CD25⁺Foxp3⁺ Treg_s, down regulate immunity and promote tumor cell growth by directly suppressing CD8⁺ and CD4⁺ T cells. Alternatively they can promote tumor growth by generating interleukin-10 (IL-10) and transforming growth factor β (TGFβ) in situ, which help tumor cells to evade the immune system.

Methods

In vivo tumor models were prepared via subcutaneous injection with a suspension of B16 melanoma cells into the left upper flank of C57BL/6 J mice. The mice were randomized into five groups: radiotherapy (RT), chemotherapy (CT), radiochemotherapy (RCT), Inteferon α (INFα) groups, and a control group. Flow cytometry was used to determine the Treg_s levels in the spleen and peripheral blood, and immunohistochemistry was performed to determine the expression levels of TGFβ and IL-10 in the tumor microenvironment.

Results

Tumor weight was significantly reduced in the CT or RCT groups (40.91 % and 41.83 %, respectively), while the reduction in tumor weight was relatively lower for the RT and IFNα groups (15.10 % and 13.15 %, respectively). The flow cytometry results showed that the ratios of CD4⁺CD25⁺Foxp3⁺ Treg_s to lymphocytes and CD4⁺ cells in the spleen and in peripheral blood were significantly decreased after treatment with IFNα (P < 0.05). Expression of TGFβ and IL-10 in the tumor microenvironment in the CT and RT groups was higher compared with the control group (P < 0.01), while the expression of TGFβ and IL-10 in the INFα group was not significantly different (P > 0.05).

Conclusions

The results show that INFα-2b inhibits cancer cell immune evasion by decreasing the levels of CD4⁺CD25⁺Foxp3⁺ Treg_s and suppressing the expression of TGFβ and IL-10 in the tumor microenvironment.

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Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats

Abstract

Background

Cancer-cachexia state frequently induces both fat and protein wasting, leading to death. In this way, the knowledge of the mechanism of drugs and their side effects can be a new feature to treat and to have success, contributing to a better life quality for these patients. Metformin is an oral drug used in type 2 diabetes mellitus, showing inhibitory effect on proliferation in some neoplastic cells. For this reason, we evaluated its modulatory effect on Walker-256 tumour evolution and also on protein metabolism in gastrocnemius muscle and body composition.

Methods

Wistar rats received or not tumour implant and metformin treatment and were distributed into four groups, as followed: control (C), Walker 256 tumour-bearing (W), metformin-treated (M) and tumour-bearing treated with metformin (WM). Animals were weighed three times a week, and after cachexia state has been detected, the rats were euthanised and muscle and tumour excised and analysed by biochemical and molecular assays.

Results

Tumour growth promoted some deleterious effects on chemical body composition, increasing water and decreasing fat percentage, and reducing lean body mass. In muscle tissue, tumour led to a decreased protein synthesis and an increased proteolysis, showing the higher activity of the ubiquitin-proteasome pathway. On the other hand, the metformin treatment likely minimised the tumour-induced wasting state; in this way, this treatment ameliorated chemical body composition, reduced the higher activities of proteolytic enzymes and decreased the protein waste.

Conclusion

Metformin treatment not only decreases the tumour growth but also improves the protein metabolism in gastrocnemius muscle in tumour-bearing rats.

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Prognostic and clinical impact of PIK3CA mutation in gastric cancer: pyrosequencing technology and literature review

Abstract

Background

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations that activate the PI3K/AKT signaling pathway have been observed in several types of carcinoma and have been associated with patient prognosis. However, the significance of PIK3CA mutations in gastric cancer remains unclear. This retrospective study investigated the relationship between PIK3CA mutations and clinical outcomes in patients with gastric cancer. Additionally, we reviewed the rate of PIK3CA mutations in gastric cancer and the association between PIK3CA mutations and prognosis in human cancers.

Methods

The study included 208 patients with gastric cancer who underwent surgical resection at Kumamoto University Hospital, Japan, between January 2001 and August 2010. Mutations in PIK3CA exons 9 and 20 were quantified by pyrosequencing assays.

Results

PIK3CA mutations were detected in 25 (12 %) of the 208 patients. Ten patients had c.1634A > G (p.E545G), 10 had c.1624G > A (p.E542K), 13 had c.1633G > A (p.E545K), nine had c.3139C > T (p.H1047R), and 1 had c.3140A > G (p.H1047Y) mutations. PIK3CA mutations were not significantly associated with any clinical, epidemiologic, or pathologic characteristic. Kaplan–Meier analysis showed no significant differences in disease-free survival (log rank P = 0.84) and overall survival (log rank P = 0.74) between patients with and without PIK3CA mutations.

Conclusions

Mutations in PIK3CA did not correlate with prognosis in patients with gastric cancer, providing additional evidence for the lack of relationship between the two.

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Mammographic density and structural features can individually and jointly contribute to breast cancer risk assessment in mammography screening: a case–control study

Abstract

Background

Mammographic density is a well-established risk factor for breast cancer. We investigated the association between three different methods of measuring density or parenchymal pattern/texture on digitized film-based mammograms, and examined to what extent textural features independently and jointly with density can improve the ability to identify screening women at increased risk of breast cancer.

Methods

The study included 121 cases and 259 age- and time matched controls based on a cohort of 14,736 women with negative screening mammograms from a population-based screening programme in Denmark in 2007 (followed until 31 December 2010). Mammograms were assessed using the Breast Imaging-Reporting and Data System (BI-RADS) density classification, Tabár's classification on parenchymal patterns and a fully automated texture quantification technique. The individual and combined association with breast cancer was estimated using binary logistic regression to calculate Odds Ratios (ORs) and the area under the receiver operating characteristic (ROC) curves (AUCs).

Results

Cases showed significantly higher BI-RADS and texture scores on average than controls (p < 0.001). All three methods were individually able to segregate women into different risk groups showing significant ORs for BI-RADS D3 and D4 (OR: 2.37; 1.32–4.25 and 3.93; 1.88–8.20), Tabár's PIII and PIV (OR: 3.23; 1.20–8.75 and 4.40; 2.31–8.38), and the highest quartile of the texture score (3.04; 1.63–5.67). AUCs for BI-RADS, Tabár and the texture scores (continuous) were 0.63 (0.57–0–69), 0.65 (0.59–0–71) and 0.63 (0.57–0–69), respectively. Combining two or more methods increased model fit in all combinations, demonstrating the highest AUC of 0.69 (0.63-0.74) when all three methods were combined (a significant increase from standard BI-RADS alone).

Conclusion

Our findings suggest that the (relative) amount of fibroglandular tissue (density) and mammographic structural features (texture/parenchymal pattern) jointly can improve risk segregation of screening women, using information already available from normal screening routine, in respect to future personalized screening strategies.

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Metabolic syndrome is associated with advanced prostate cancer in patients treated with radical retropubic prostatectomy: results from a multicentre prospective study

Abstract

Background

Prostate cancer (PCa) is the most common non-skin cancer in USA and the second leading cause of cancer death in Western Countries. Despite the high mortality associated with PCa, the only established risk factors are age, race and family history. A possible association between metabolic syndrome (MetS) and PCa was firstly described in 2004 and several subsequent studies in biopsy cohorts have shown conflicting results. Aim of our multicentre prospective study was to investigate the association between MetS and PCa in men undergoing radical prostatectomy (RP).

Methods

From January 2012 to June 2015, 349 consecutive men undergoing RP for PCa at three centres in Italy were enrolled into a prospective database. Body Mass Index (BMI) as well as waist circumference was measured before RP. Blood samples were also collected and tested for total PSA, fasting glucose, triglycerides and HDLs. Blood pressure was also recorded. We evaluated the association between MetS, defined according to Adult Treatment Panel III, PCa stage (advanced stage defined as pT ≥ 3 or N1) and grade (high grade defined as Gleason Score ≥ 4 + 3) using logistic regression analyses.

Results

Median age and preoperative PSA levels were 66 years (IQR: 61-69) and 7 ng/ml (IQR: 5-10), respectively. Median BMI was 26.12 kg/m² (IQR 24-29) with 56 (16 %) obese (BMI ≥ 30 kg/m²) patients and 87 (25 %) patients with MetS. At pathological evaluation, advanced PCa and high-grade disease were present in 126 (36 %) and 145 (41.5 %) patients, respectively. MetS was significantly associated with advanced PCa (45/87, 51 % vs 81/262, 31 %; p = 0.008) and high-grade disease (47/87, 54 % vs 98/262, 37 %; p = 0.001). On multivariable analysis, MetS was an independent predictor of pathological stage ≥ pT3a or N1 (OR: 2.227; CI: 1.273-3.893; p = 0.005) and Gleason score ≥ 4 + 3 (OR: 2.007, CI: 1.175-3.428; p = 0.011).

Conclusions

We firstly demonstrated in a European radical retropubic prostatectomy cohort study that MetS is associated with an increased risk of high-grade and advanced prostate cancer. Further studies with long term follow-up should evaluate the impact of Mets on PCa survival.

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EGFR gene amplification is relatively common and associates with outcome in intestinal adenocarcinoma of the stomach, gastro-oesophageal junction and distal oesophagus

Abstract

Background

Approximately 50 % of gastric adenocarcinomas belong to a molecular subgroup characterised by chromosomal instability and a strong association with the intestinal histological subtype. This subgroup typically contains alterations in the receptor tyrosine kinase–RAS pathway, for example EGFR or HER2 gene amplifications leading to protein overexpression. In clinical practice, HER2 overexpressing metastatic gastric cancer is known to respond to treatment with anti-HER2 antibodies. By contrast, anti-EGFR antibodies have not been able to provide survival benefit in clinical trials, which, however, have not included patient selection based on the histological subtype or EGFR gene copy number analysis of the tumours. To examine the role of EGFR as a potential biomarker, we studied the prevalence, clinicopathological associations as well as prognostic role of EGFR and HER2 expression and gene amplification in intestinal adenocarcinomas of the stomach, gastro-oesophageal junction and distal oesophagus.

Methods

Tissue samples from 220 patients were analysed with EGFR and HER2 immunohistochemistry. Those samples with moderate/strong staining intensity were further analysed with silver in situ hybridization to quantify gene copy numbers. The results were associated with clinical patient characteristics and survival.

Results

Moderate/strong EGFR protein expression was found in 72/220 (32.7 %) and EGFR gene amplification in 31/220 (14.1 %) of the tumours, while moderate/strong HER2 protein expression was detected in 31/220 (14.1 %) and HER2 gene amplification in 29/220 (13.2 %) of the tumours. EGFR and HER2 genes were co-amplified in eight tumours (3.6 %). EGFR gene amplification was more common in tumours of distal oesophagus/gastro-oesophageal junction/cardia than in those of gastric corpus (p = 0.013). It was associated with shortened time to cancer recurrence (p = 0.026) and cancer specific survival (p = 0.033).

Conclusions

EGFR gene amplification is relatively common in intestinal adenocarcinomas and associates with decreased survival. It is rarely concurrent with HER2 gene amplification, suggesting that anti-EGFR therapies might be applicable to some patients not eligible for anti-HER2 treatment. Analogous to HER2 testing, determination of EGFR gene amplification status in concert with immunohistochemistry could improve the specificity of patient selection when investigating the possible benefits of anti-EGFR therapies in the treatment of gastric adenocarcinomas.

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Carbon ion therapy (C12) for high-grade malignant salivary gland tumors (MSGTs) of the head and neck: do non-ACCs profit from dose escalation?

Abstract

Purpose

To evaluate the use of high-dose radiotherapy using carbon ions (C12) on non-adenoid cystic malignant salivary gland tumors (MSGT).

Patients and methods

Between 2009 and 2013, patients with biopsy-proven non-ACC MSGT histologies of the head and neck received a combined regimen of IMRT plus C12 boost. Treatment toxicity (CTC v3), response (RECIST 1.1), control and survival rates were retrospectively analyzed.

Results

40 patients with pathologically confirmed non-ACC MSGT (T4: 45 %; N+: 40 %; gross residual: 58 %; mucoepidermoid carcinoma (MEC): 45 %; adenocarcinoma: 20 %) were treated with a median of 74 GyE (80 Gy BED). Chemoradiation was given in 5 patients with MEC. Grade III acute toxicity was observed in up to 15 % (mucositis, dermatitis, dysphagia), no higher-grade late toxicity occurred to date. At a follow-up of 25.5 months, LC, and PFS at 2 and 3 years are 81.5 % (LC) and 66.8 % (PFS), OS at 2 and 3 years is 83.6 % and 72.8 %. Most frequent site of disease progression was distant metastasis. Histologic subtype correlated with LC and PFS. Resection status (gross vs microscopic disease) had no significant effect on LC, PFS, or OS.

Conclusion

The treatment is well tolerated, no higher grade late effects were observed. Considering the negative pre-selection, LC, PFS and OS are promising. While histology and site of origin significantly influenced control and survival rates, resection status did not, potentially due to the effect of dose escalation.

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Titanium peroxide nanoparticles enhanced cytotoxic effects of X-ray irradiation against pancreatic cancer model through reactive oxygen species generation in vitro and in vivo

Abstract

Background

Biological applications of nanoparticles are rapidly increasing, which introduces new possibilities to improve the efficacy of radiotherapy. Here, we synthesized titanium peroxide nanoparticles (TiOxNPs) and investigated their efficacy as novel agents that can potently enhance the effects of radiation in the treatment of pancreatic cancer.

Methods

TiOxNPs and polyacrylic acid-modified TiOxNPs (PAA-TiOxNPs) were synthesized from anatase-type titanium dioxide nanoparticles (TiO₂NPs). The size and morphology of the PAA-TiOxNPs was evaluated using transmission electron microscopy and dynamic light scattering. The crystalline structures of the TiO₂NPs and PAA-TiOxNPs with and without X-ray irradiation were analyzed using X-ray absorption. The ability of TiOxNPs and PAA-TiOxNPs to produce reactive oxygen species in response to X-ray irradiation was evaluated in a cell-free system and confirmed by flow cytometric analysis in vitro. DNA damage after X-ray exposure with or without PAA-TiOxNPs was assessed by immunohistochemical analysis of γ-H2AX foci formation in vitro and in vivo. Cytotoxicity was evaluated by a colony forming assay in vitro. Xenografts were prepared using human pancreatic cancer MIAPaCa-2 cells and used to evaluate the inhibition of tumor growth caused by X-ray exposure, PAA-TiOxNPs, and the combination of the two.

Results

The core structures of the PAA-TiOxNPs were found to be of the anatase type. The TiOxNPs and PAA-TiOxNPs showed a distinct ability to produce hydroxyl radicals in response to X-ray irradiation in a dose- and concentration-dependent manner, whereas the TiO₂NPs did not. At the highest concentration of TiOxNPs, the amount of hydroxyl radicals increased by >8.5-fold following treatment with 30 Gy of radiation. The absorption of PAA-TiOxNPs enhanced DNA damage and resulted in higher cytotoxicity in response to X-ray irradiation in vitro. The combination of the PAA-TiOxNPs and X-ray irradiation induced significantly stronger tumor growth inhibition compared to treatment with either PAA-TiOxNPs or X-ray alone (p < 0.05). No apparent toxicity or weight loss was observed for 43 days after irradiation.

Conclusions

TiOxNPs are potential agents for enhancing the effects of radiation on pancreatic cancer and act via hydroxyl radical production; owing to this ability, they can be used for pancreatic cancer therapy in the future.

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Podoplanin associates with adverse postoperative prognosis of patients with clear cell renal cell carcinoma

Abstract

Podoplanin, a transmembrane sialomucin-like glycoprotein, was recently shown to be involved in tumor progression and metastasis for its potential role in facilitating platelet-based tumor embolization and promigratory phenotype of cancer cells. In this study, we assessed the clinical significance of tumoral podoplanin expression in 295 patients with clear cell renal cell carcinoma (ccRCC) through immunohistochemistry on tissue microarrays and analyzed the staining intensity quantitatively. Univariate analysis suggested an adverse prognostic effect of high tumoral podoplanin expression on patients' overall survival (OS) and recurrence free survival (RFS) (P<0.001 for both). In multivariate analysis, the staining intensity used as either a continuous or dichotomous variable, was still an independent adverse prognostic factor for patient survival (OS, P<0.001, RFS, P<0.001 for continuous; OS, P<0.001, RFS, P=0.002 for dichotomous). Moreover, stratified analysis identified a higher prognostic power in the intermediate/high risk patient groups. After utilizing those parameters in the validated multivariate analysis, two nomograms were constructed to predict ccRCC patients' OS and RFS (c-index 0.815 and 0.805, respectively), and performed better than existed integrated models (P<0.001 for all comparisons). In conclusion, high tumoral podoplanin expression could independently predict an adverse clinical outcome for ccRCC patients, and it might be used for future clinical decision making and therapeutic developments.

This article is protected by copyright. All rights reserved.

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Carbon ion therapy (C12) for high-grade malignant salivary gland tumors (MSGTs) of the head and neck: do non-ACCs profit from dose escalation?

To evaluate the use of high-dose radiotherapy using carbon ions (C12) on non-adenoid cystic malignant salivary gland tumors (MSGT).

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Titanium peroxide nanoparticles enhanced cytotoxic effects of X-ray irradiation against pancreatic cancer model through reactive oxygen species generation in vitro and in vivo

Biological applications of nanoparticles are rapidly increasing, which introduces new possibilities to improve the efficacy of radiotherapy. Here, we synthesized titanium peroxide nanoparticles (TiOxNPs) and i...

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Patient-centered support in the survivorship care transition: Outcomes from the Patient-Owned Survivorship Care Plan Intervention

BACKGROUND

To the authors' knowledge, few studies to date have evaluated the effects of survivorship care planning on the care transition process from specialty cancer care to self-management and primary care, patient experience, or health outcomes. The Patient-owned Survivorship Transition Care for Activated, Empowered survivors (POSTCARE) is a single coaching encounter based on the Chronic Care Model that uses motivational interviewing techniques to engage survivors of breast cancer. The current study examined the effects of the POSTCARE intervention on patient outcomes and care coordination.

METHODS

A total of 79 survivors of American Joint Commision on Cancer TNM System stage 0 to IIIB breast cancer were randomized to POSTCARE (40 patients) or usual care (39 patients). Patient outcomes were assessed using the 36-Item Short Form Health Survey (SF-36), Social/Role Activities Limitations, Self-Efficacy for Managing Chronic Disease 6-Item Scale, the Patient Activation Measure–Short Form, and Patient Health Questionnaire depression scale at baseline and at 3-month follow-up. Care coordination was assessed using confirmed primary care physician visits and reported discussion of the survivorship care plan at the 3-month follow-up. Logistic and linear regression analyses were conducted to examine the effect of POSTCARE on selected outcomes.

RESULTS

Participants in the intervention group versus those receiving usual care demonstrated significantly higher self-reported health (F-statistic (3,71), 3.63; P =.017) and lower social role limitations (F (3,70), 3.82; P =.014) and a trend toward greater self-efficacy (F (3,69), 2.51; P = .07). Three quality-of-life domains reached clinically meaningful improvement at the 3-month follow-up, including physical role (P =.0009), bodily pain (P =.03), and emotional role (P =.04).

CONCLUSIONS

The POSTCARE intervention appeared to have a positive impact on patient outcomes and demonstrated promise as a strategy with which to improve survivors' experience, care coordination, and health outcomes. Cancer 2016. © 2016 American Cancer Society.

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Nutrition Therapy in the Organ Donor: Theoretical Benefits and Barriers to Implementation

Abstract

While standardized organ donor management has maximized the number of organs successfully transplanted in the past 10 years, organ donor management prior to the procurement operation does not typically include nutrition therapy. The value of providing nutrition therapy in critically ill patients relates to reductions seen in infection and multiple organ failure, especially with early enteral feeding. Preventing infection and maintaining organ function prior to organ transplantation are key strategies in the management of the donor population. This paper discusses the rationale for providing nutrition therapy to critically ill brain-dead organ donors, highlighting potential benefits, issues with implementation, the importance of timing, and the potential risks which may be involved. While little experience exists in the literature, the potential benefits which might be incurred warrant consideration for initiating nutrition therapy in this patient population.

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Low absolute CD4 + T cell counts in peripheral blood are associated with inferior survival in follicular lymphoma

Abstract

Host immunity and tumor microenvironment significantly influence follicular lymphoma (FL) outcomes. Lymphopenia has been identified as a negative prognostic factor for FL. However, there is limited data regarding prognostic value of peripheral blood T lymphocyte subsets, especially absolute CD4⁺ T cell counts (ACD4C) in FL. We studied 127 consecutive FL patients to investigate whether peripheral blood ACD4C or absolute monocytes (AMC) at diagnosis had an impact on FL prognosis. In our cohort, both low ACD4C and high AMC were the parameters associated with inferior progression-free survival (PFS) (P = 0.021 and P = 0.013, respectively) and inferior overall survival (OS) (P = 0.020 and P = 0.005, respectively) by univariate analysis. Multivariate analysis revealed that only low ACD4C was statistically significant in worse PFS (hazard ratio, 2.811; 95 % confidence interval, 1.137−6.950; P = 0.025) and shorter OS (hazard ratio, 3.393; 95 % confidence interval, 1.037−11.105; P = 0.043) independent of FLIPI-2. Evaluation of blood ACD4C could be a useful indicator of outcome in previously untreated FL patients.

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Cytotoxicity of withasteroids: withametelin induces cell cycle arrest at G2/M phase and mitochondria-mediated apoptosis in non-small cell lung cancer A549 cells

Abstract

Considerable interest has been gained by withasteroids because of their structural uniqueness and wide spectrum of biological activities. However, limited systematic studies for proving their cytotoxic potential have so far been reported. Hence, an attempt was made to test the cytotoxicity of six withasteroids viz., withametelin (WM), withaphysalin D, withaphysalin E, 12-deoxywithastramonolide, Withaperuvin B, and physalolactone against A549, HT-29, and MDA-MB-231 cancer cell lines. Significant cytotoxic effect of WM against A549 cells (IC₅₀ value of 6.0 μM), MDA-MB-231 cells (IC₅₀ value of 7.6 μM), and HT-29 cells (IC₅₀ value of 8.2 μM) was observed. Withaperuvin B and physalolactone were found to be effective against MDA-MB-231 cells. The significantly active WM arrested the A549 cells at G2/M phase and downregulated the expression of G2/M regulatory proteins such as cdc2, cyclin B1, and cdc25C. Apoptosis induced by WM in A549 cells was associated with the generation of ROS and depletion of MMP. Furthermore, WM treatment resulted in Bax upregulation, Bcl-2 downregulation, translocation of cytochrome c to mitochondria, activation of caspase-9 and −3, and PARP cleavage corroborating the apoptosis induction through intrinsic apoptotic pathway. Thus, WM possessing broader cytotoxic effect is a promising lead molecule which has the potential to be developed as a new therapeutic agent for NSCLC.

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Facilitators of Survivorship Care Among Underserved Breast Cancer Survivors: a Qualitative Study

Abstract

Research investigating facilitators of survivorship care among underserved breast cancer survivors (BCS) is sparse. This study aimed to explore facilitators of survivorship care among underserved BCS within the first 5 years following chemotherapy, radiation, or surgery for breast cancer. In-depth interviews were conducted, using a semi-structured interview guide, with underserved BCS exploring survivorship care experiences. Content analysis of the verbatim transcripts was applied, and results were summarized according to themes related to facilitators of breast cancer survivorship care. Interviews were conducted with 25 BCS. Eight main themes were identified: coordination of care; positive perceptions of health care providers; communication between patient and health care providers; financial and insurance facilitators; information, classes, and programs provided; assistance provided by organizations and health care professionals; transportation facilitators; and job flexibility. This study provides a comprehensive look at facilitators of survivorship care among underserved BCS. BCS endorsed several facilitators of their survivorship care, mainly at the interpersonal, organizational, and societal level. This study adds to the research literature on catalysts of care among underserved BCS. Results from this study are currently being used to inform a patient navigation intervention to facilitate care among this population.

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Cancers, Vol. 8, Pages 64: A Perspective of Immunotherapy for Prostate Cancer

In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa.

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Clinical significance of mitofusin-2 and its signaling pathways in hepatocellular carcinoma

Abstract

Background

The mitochondrial GTPase mitofusin-2 (MFN2) gene encodes a mitochondrial membrane protein that can induce apoptosis of hepatocellular carcinoma (HCC) via the mitochondrial apoptotic pathway, as validated in our previous research. However, little is known of the clinical significance of MFN2 expression and its signaling pathways in HCC.

Methods

MFN2 mRNA expression in tumor and adjacent non-tumor tissues from 115 patients with HCC was investigated using quantitative real-time PCR. The association of the MFN2 mRNA expression level with clinical and pathological parameters was evaluated statistically, while a comparative microarray analysis was used to identify MFN2 signaling pathways in HepG2 cells.

Results

MFN2 was significantly (p < 0.0001) downregulated in HCC tissues. Low MFN2 expression was significantly correlated with sex and preoperative alpha-fetoprotein (p < 0.05). Both a Kaplan–Meier survival curve and multivariate analyses showed that MFN2 was related to overall survival. A comparative gene expression microarray revealed 211 upregulated (58 %) and 153 downregulated (42 %) genes. Eighteen pathways were identified as the most significant pathways correlated with MFN2.

Conclusions

Low MFN2 expression in HCC indicated a worse overall survival. Crucial signaling molecules such as PI3K-AKT, cytokine receptor, and focal adhesion may participate in MFN2-mediated signaling pathway changes in HCC.

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Integration of legal aspects and human rights approach in palliative care delivery—The Nyeri hospice model

David Musyoki, Sarafina Gichohi, Johnson Ritho and Zipporah Ali

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Kenya Hospices and Palliative Care association: integrating palliative care in public hospitals in Kenya

Zipporah Ali

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The Island Hospice model of palliative care

Thembelihle Khumalo and Valerie Maasdorp

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Interventions geared towards strengthening the health system of Namibia through the integration of palliative care

Rachel Freeman, Emmanuel BK Luyirika, Eve Namisango and Fatia Kiyange

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Best practices in developing a national palliative care policy in resource limited settings: lessons from five African countries

Emmanuel BK Luyirika, Eve Namisango, Eunice Garanganga, Lidia Monjane, Ntombi Ginindza, Gugulethu Madonsela and Fatia Kiyange

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Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

Breast cancer is genetically and clinically heterogeneous, which makes it challenging to identify effective patient-specific therapies. Although mortality due to breast cancer in the United States has decreased, more than 40,000 women in the United States still die from this disease each year.…

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Adaptive Randomization of Neratinib in Early Breast Cancer

The treatment of aggressive, locally advanced breast cancers increasingly includes neoadjuvant therapy before surgical resection, thus providing a window of opportunity to tailor treatments on the basis of early assessments of the molecular characteristics of the cancer and their response to…

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I-SPY 2 — Toward More Rapid Progress in Breast Cancer Treatment

Clinical trials of systemic therapy for operable breast cancer are evolving. Our understanding of breast cancer as a family of biologically distinct diseases has implications for patient selection and the optimization of drug choices. In addition, there is a growing dissatisfaction with trials of…

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I-SPY 2 — A Glimpse of the Future of Phase 2 Drug Development?

The articles by Rugo et al. (pages 23–33) and Park et al. (pages 11–22) in this issue of the Journal report results from the I-SPY (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis) 2 platform, a promising adaptive strategy for matching…

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The molecular signature of breast cancer metastasis to bone.

Distant metastasis during the advanced stage of malignant tumor progression can cause considerable morbidity in cancer patients. Bone is known to be one of the most common sites of distant metastasis in patients with breast cancer (BC). BC metastases in bone are associated with excessive skeletal complications. These complications can be fatal and reduce quality of life of patients. It is important to understand the metastatic process of BC to bone to improve quality of life and design new therapeutic methods. At present, the molecular mechanisms leading to the BC metastasis to bone are not fully understood. Studying the molecular basis of BC metastasis to bone might improve our insight into this complex process. In addition, it can provide novel approaches for designing advanced and effective targeted therapies. The present article aimed to review the published papers on the molecular basis of the metastatic process of BC to bone, focusing on involved genes and signaling networks. Furthermore, we propose potential therapeutic targets that may be more effective for the inhibition and treatment of BC metastasis to bone. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Next-generation sequencing in patients with advanced cancer: are we ready for widespread clinical use? A single institute's experience.

The next-generation sequencing (NGS) assay targeting cancer-relevant genes has been adopted widely for use in patients with advanced cancer. The primary aim of this study was to assess the clinical utility of commercially available NGS. We retrospectively collected demographic and clinicopathologic data, recommended therapy, and clinical outcomes of 30 patients with a variety of advanced solid tumors referred to Foundation Medicine NGS. The initial pathologic examination was performed at the pathology department of the referring hospital. The comprehensive clinical NSG assay was performed on paraffin-embedded tumor samples using the Clinical Laboratory Improvement Amendments-certified FoundationOne platform. The median number of genomic alterations was 3 (0-19). The median number of therapies with potential benefit was 2 (0-8). In 12 cases, a comprehensive clinical NGS assay did not indicate any therapy with potential benefit according to the genomic profile. Ten of the 30 patients received treatments recommended by genomic profile results. In six of the 10 cases, disease progressed within 2 months and four patients died within 3 months of treatment initiation. Three of the 30 patients benefited from a comprehensive clinical NGS assay and the subsequent recommended therapy. The median PFS was 12 weeks (95% confidence interval 10-57) in patients treated with molecularly targeted agents chosen on the basis of tumor genomic profiling versus 48 weeks (95% confidence interval 8-38) in the control group treated with physician choice therapy (P=0.12). Our study suggests that NGS can detect additional treatment targets in individual patients, but prospective medical research and appropriate clinical guidelines for proper clinical use are vital. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Status quo of p53 in the treatment of tumors.

The p53 gene is pivotal for oncogenesis in a combination of mutations in oncogenes and antioncogenes. The ubiquitous loss of the p53 pathway in human cancers has generated considerable interest in developing p53-targeted cancer therapies, but current ideas and approaches targeting p53 are conflicting. Current researches focus on cancer-selective drugs with therapeutic strategies that both activate and inhibit p53. As p53 is ubiquitously lost in human cancers, the strategy of exogenous p53 addition is reasonable. However, p53 acts not equally in all cell types; thus, individualized p53 therapy is the direction of future research. To clarify the controversies on p53 for improvement of future antitumor studies, the review focuses on the available technological protocols, including their advantages and limitations in terms of future therapeutic use of p53 in the management of tumors. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Outcomes of vascularized versus non-vascularized lymph node transplant in animal models for lymphedema. Review of the literature

Lymph node transfer has been performed to treat lymphedema for several years. The goal of this procedure is to provide a bridge between the lymphatic system distal and proximal to the lymph node dissection. There is a lack of consensus about the necessity of an additional vascular anastomosis for the transplanted lymph nodes. A systematic literature search in Cochrane Library database CENTRAL, MEDLINE, and EMBASE of animal studies using lymph node transplantation with and without additional vascularization was performed in March 2016. The strategy used for the search was: (("Models, Animal"[Mesh]) AND (("Lymphedema"[Mesh]) OR "Lymph Nodes"[Mesh]) OR "Lymph Node Excision"[Mesh])) AND ((vascularized lymph node transfer) OR ((non-vascularized lymph node transfer) OR lymph node graft)). The primary outcomes were: survival of transplanted lymph node and lymphatic vessel regeneration. Sixteen studies were included. Vascularization and the use of growth factors were significantly associated with lymph node survival. Lymphatic vessels regeneration was independent from vascularization. According to the results of the current study, additional vascular anastomosis might improve the transplanted lymph node survival. Further studies in both experimental and clinical setting are needed in order to support it. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Rectal cancers with microscopic circumferential resection margin involvement (R1 resections): Survivals, patterns of recurrence, and prognostic factors

Background and Objectives

We have reviewed our series of rectal cancer patients with circumferential resection margin involvement (R1) with particular regard to survival and prognostic factors.

Methods

R1 rectal cancer patients undergoing surgery at the Leicester Royal Infirmary between 1998 and 2008. Age, gender, radiological, and pathological tumor characteristics, neoadjuvant and adjuvant therapies were examined as prognostic factors on the overall survival (OS) and disease-free survival (DFS) at 5-year follow-up.

Results

A total of 885 rectal cancers were reviewed. Six hundred ninety-nine patients underwent a mesorectal excision and 71 of them were R1 resections (12.9%). OS was 43.7% (CI95% 33.5–53.8%; median survival 39 months). DFS was 57.4% (CI95% 43.0–71.8%; median survival 31 months). Pelvic recurrence rate occurred in 16 patients (26.2%, CI95% 16.5–36.0%), systemic recurrence rate in 23 patients (37.7%, CI95% 25.5–49.9%). At Cox-regression LNR and adjuvant chemotherapy were associated with both OS and DFS. No significant association was found between OS or DFS and adjuvant radiotherapy.

Conclusions

In our series of R1 patients, the rates of local recurrence and OS at 5 years were 26.2% and 43.7%, respectively. Factors influencing systemic recurrences (LNR, adjuvant chemotherapy) are more associated with OS and DFS than those potentially affecting locoregional recurrences (adjuvant radiotherapy). J. Surg. Oncol. 2016;9999:1-7. © 2016 Wiley Periodicals, Inc.

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Obesity is not associated with increased morbidity in patients undergoing cytoreductive surgery with intraperitoneal chemotherapy

Background and Objectives

Recent single-institutional series have examined the relationship of body mass index (BMI) in patients undergoing cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) generally without significant increase in serious complications with increasing BMI. This study evaluates the impact of BMI on complication rates using a national cohort.

Methods

The ACS NSQIP database was queried for patients undergoing concurrent CRS with IPC (2005–2012). Death and serious morbidity (DSM) was the primary outcome. Statistical analyses were performed to determine significant associations between peri-operative factors and DSM.

Results

Of 1,085 patients, there were 30.4% (n = 330) obese (BMI >30) and 32.1% (n = 348) normal weight (BMI 18.5–24.9) patients. DSM rates did not differ between these groups (P = 0.853). Obese patients were more likely to experience post-operative wound (P = 0.017) and renal (P = 0.002) complications. Hypoalbuminemia (OR 7.34; 95% CI 2.27–23.73), prolonged operative time (OR 3.02; 95% CI 1.83–4.97) and concomitant liver resection (OR 3.29; 95% CI 1.31–8.28) were independent risk factors for DSM among obese patients.

Conclusions

Obesity is not significantly associated with DSM in patients undergoing CRS/IPC, and should not be a major deterrence for surgery. However, obese patients are more likely to experience wound and renal complications and hypoalbuminemia is a strong preoperative risk factor. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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