Next Generation Sequencing in Diffuse Large B Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Purpose: Next Generation Sequencing (NGS) has detailed the genomic characterization of Diffuse Large B Cell Lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials. Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature data and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20+ de novo DLBCL in the prospective, multicenter and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell of origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays. Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that Activated B Cell-like (ABC), Germinal Center B-cell like (GCB) and Primary Mediastinal B-cell Lymphoma (PMBL) are frequently affected by mutations in NFkB, epigenetic, and JAK-STAT pathways respectively. Novel truncating immunity pathway, ITPKB, MFHAS1 and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses. Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting subtypes' molecular heterogeneity and identifying somatic mutations with therapeutic and prognostic impact.

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NDUFA4L2 fine-tunes oxidative stress in hepatocellular carcinoma

Purpose: Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of pro-tumorigenic responses through hypoxia-inducible factor-1 (HIF-1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen. Experimental Design: Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O2) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and non-tumorous liver tissues were analyzed by qRT-PCR. Student's t test and Kaplan-Meier analysis were used for clinicopathological correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor. Results: NDUFA4L2 was drastically over-expressed in human HCC and induced by hypoxia. NDUFA4L2 over-expression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF-1-regulated in HCC cells. Inactivation of HIF-1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo. HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2. Conclusions: Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 over-expression may be suitable candidates for HIF inhibitor treatment.

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Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer

IDH1 and IDH2 are homodimeric enzymes that catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) and concomitantly produce reduced nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+. Mutations in the genes encoding IDH1 and IDH2 have recently been found in a variety of human cancers, most commonly glioma, acute myeloid leukemia (AML), chondrosarcoma, and intrahepatic cholangiocarcinoma. The mutant protein loses its normal enzymatic activity and gains a new ability to produce the 'oncometabolite' R(-)-2-hydroxyglutarate (2HG). 2-HG competitively inhibits α-KG-dependent enzymes which play crucial roles in gene regulation and tissue homeostasis. Expression of mutant IDH impairs cellular differentiation in various cell lineages and promotes tumor development in cooperation with other cancer genes. First-generation inhibitors of mutant IDH have entered clinical trials and have shown encouraging results in patients with IDH2 mutant AML. This article summarizes recent progress in our understanding of the role of mutant IDH in tumorigenesis.

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Pan-cancer immunogenomic perspective on the tumor microenvironment based on PD-L1 and CD8 T cell infiltration

Purpose: There is currently no reliable biomarker to predict who would benefit from anti-PD-1/PD-L1 inhibitors. We comprehensively analyzed the immunogenomic properties in The Cancer Genome Atlas (TCGA) according to the classification of tumor into four groups based on PD-L1 status and tumor-infiltrating lymphocyte recruitment (TIL), a combination that has been suggested to be theoretically reliable biomarker of anti-PD-1/PD-L1 inhibitors. Experimental design: The RNA expression levels of PD-L1 and CD8A in the samples in the pan-cancer database of TCGA (N=9,677) were analyzed. Based on their median values, the samples were classified into four tumor microenvironment immune types (TMITs). The mutational profiles, PD-L1 amplification, and viral association of the samples were compared according to the four TMITs. Results: The proportions of TMIT I, defined by high PD-L1 and CD8A expression, were high in lung adenocarcinoma (67.1%) and kidney clear cell carcinoma (64.8%) among solid cancers. The number of somatic mutations and the proportion of microsatellite instable-high tumor in TMIT I were significantly higher than those in other TMITs, respectively (P < 0.001). CD274 amplification and oncogenic virus infection were significantly associated with TMIT I, respectively (P < 0.001). A multivariate analysis confirmed that the number of somatic mutations, PD-L1 amplification, and Epstein-Barr virus/human papillomavirus infection were independently associated with TMIT I. Conclusions: TMIT I is associated with a high mutational burden, PD-L1 amplification, and oncogenic viral infection. This integrative analysis highlights the importance of the assessment of both PD-L1 expression and TIL recruitment to predict responders to immune checkpoint inhibitors.

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GPU-Based Simulation of Ultrasound Imaging Artifacts for Cryosurgery Training

This study presents an efficient computational technique for the simulation of ultrasound imaging artifacts associated with cryosurgery based on nonlinear ray tracing. This study is part of an ongoing effort to develop computerized training tools for cryosurgery, with prostate cryosurgery as a development model. The capability of performing virtual cryosurgical procedures on a variety of test cases is essential for effective surgical training. Simulated ultrasound imaging artifacts include reverberation and reflection of the cryoprobes in the unfrozen tissue, reflections caused by the freezing front, shadowing caused by the frozen region, and tissue property changes in repeated freeze–thaw cycles procedures. The simulated artifacts appear to preserve the key features observed in a clinical setting. This study displays an example of how training may benefit from toggling between the undisturbed ultrasound image, the simulated temperature field, the simulated imaging artifacts, and an augmented hybrid presentation of the temperature field superimposed on the ultrasound image. The proposed method is demonstrated on a graphic processing unit at 100 frames per second, on a mid-range personal workstation, at two orders of magnitude faster than a typical cryoprocedure. This performance is based on computation with C++ accelerated massive parallelism and its interoperability with the DirectX-rendering application programming interface.

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Customized Tool for the Validation of Optical Coherence Tomography in Differentiation of Prostate Cancer

Objective:

To design and demonstrate a customized tool to generate histologic sections of the prostate that directly correlate with needle-based optical coherence tomography pullback measurements.

Materials and Methods:

A customized tool was created to hold the prostatectomy specimens during optical coherence tomography measurements and formalin fixation. Using the tool, the prostate could be sliced into slices of 4 mm thickness through the optical coherence tomography measurement trajectory. In this way, whole-mount pathology slides were produced in exactly the same location as the optical coherence tomography measurements were performed. Full 3-dimensional optical coherence tomography pullbacks were fused with the histopathology slides using the 3-dimensional imaging software AMIRA, and images were compared.

Results:

A radical prostatectomy was performed in a patient (age: 68 years, prostate-specific antigen: 6.0 ng/mL) with Gleason score 3 + 4 = 7 in 2/5 biopsy cores on the left side (15%) and Gleason score 3 + 4 = 7 in 1/5 biopsy cores on the right side (5%). Histopathology after radical prostatectomy showed an anterior located pT2cNx adenocarcinoma (Gleason score 3 + 4 = 7). Histopathological prostate slides were produced using the customized tool for optical coherence tomography measurements, fixation, and slicing of the prostate specimens. These slides correlated exactly with the optical coherence tomography images. Various structures, for example, Gleason 3 + 4 prostate cancer, stroma, healthy glands, and cystic atrophy with septae, could be identified both on optical coherence tomography and on the histopathological prostate slides.

Conclusion:

We successfully designed and applied a customized tool to process radical prostatectomy specimens to improve the coregistration of whole mount histology sections to fresh tissue optical coherence tomography pullback measurements. This technique will be crucial in validating the results of optical coherence tomography imaging studies with histology and can easily be applied in other solid tissues as well, for example, lung, kidney, breast, and liver. This will help improve the efficacy of optical coherence tomography in cancer detection and staging in solid organs.

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MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells

Abstract

Background

Emerging evidence demonstrates that microRNAs (miRNAs) play an important role in regulation of cell growth, invasion and metastasis through inhibiting the expression of their targets. It has been reported that miR-130a-3p controls cell growth, migration and invasion in a variety of cancer cells. However, it is unclear whether miR-130a-3p regulates epithelial-mesenchymal transition (EMT) in drug resistant cancer cells. Therefore, in the current study, we explore the role and molecular mechanisms of miR-130a-3p in gemcitabine resistant (GR) hepatocellular carcinoma (HCC) cells.

Methods

The real-time RT-PCR was used to measure the miR-130a-3p expression in GR HCC cells compared with their parental cells. The wound healing assay was conducted to determine the cell migratory activity in GR HCC cells treated with miR-130a-3p mimics. The migration and invasion assays were also performed to explore the role of miR-130a-3p in GR HCC cells. Western blotting analysis was used to measure the expression of Smad4, E-cadherin, Vimentin, and MMP-2 in GR HCC cells after depletion of Smad4. The luciferase assay was conducted to validate whether Smad4 is a target of miR-130a-3p. The student t-test was used to analyze our data.

Results

We found the down-regulation of miR-130a-3p in GR HCC cells. Moreover, we validate the Smad4 as a potential target of miR-130a-3p. Furthermore, overexpression of miR-130a-3p suppressed Smad4 expression, whereas inhibition of miR-130a-3p increased Smad4 expression. Consistently, overexpression of miR-130a-3p or down-regulation of Smad4 suppressed the cell detachment, attachment, migration, and invasion in GR HCC cells.

Conclusions

Our findings provide a molecular insight on understanding drug resistance in HCC cells. Therefore, activation of miR-130a-3p or inactivation of Smad4 could be a novel approach for the treatment of HCC.

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Interaction between MLL3 genetic polymorphisms, smoking, and alcohol drinking in laryngeal cancer: a case–control study

Abstract

A previous study indicated that MLL3 genetic polymorphisms were associated with human cancer. However, whether MLL3 genetic variants are associated with the risk of laryngeal cancer is not clear. This study investigated the association between MLL3 gene polymorphisms and laryngeal cancer in a Chinese population. Four polymorphisms of the MLL3 gene (rs6943984, rs4725443, rs3800836, rs6464211) were genotyped using the TaqMan method in 592 patients with larynx cancer and 602 age- and sex-matched noncancer controls. We found that rs6943984 and rs4725443 of the MLL3 gene were significantly associated with the risk of larynx cancer after Bonferroni correction. The minor allele A for rs6943984 was associated with increased larynx cancer risk (P < 0.001, OR = 1.960, 95% CI = 1.587–2.420). C allele frequency (0.151) for rs4725443 was significantly higher in the case group than the control group (0.072, P < 0.001). Haplotype analyses showed that haplotypes A-T-A-C and G-T-G-C increased the risk of laryngeal cancer (OR = 2.406, 95% CI: 1.820–3.180, P < 0.001; OR = 1.399, 95% CI: 1.180–1.659, respectively), and haplotypes G-T-A-C and G-T-G-T significantly reduced the risk of laryngeal cancer (OR = 0.332, 95% CI: 0.271–0.408, P < 0.001; OR = 0.742, 95% CI: 0.607–0.908, respectively). We also found that MLL3 rs6943984 and rs4725443 polymorphisms had synergistic effects with smoking or alcohol drinking for the risk of laryngeal cancer. This study indicated that MLL3 genetic polymorphisms and haplotypes were associated with larynx cancer in a Chinese population. There was a mutually synergistic effect between smoking, alcohol drinking, and MLL3 gene polymorphisms for laryngeal cancer.

This study indicated that MLL3 genetic polymorphisms and haplotypes were associated with larynx cancer in a Chinese population. There was a mutually synergistic effect between smoking, alcohol drinking, and MLL3 gene polymorphisms for laryngeal cancer.

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Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy

The genetic modification and characterization of T-cells with chimeric antigen receptors (CARs) allow functionally distinct T-cell subsets to recognize specific tumor cells. The incorporation of costimulatory molecules or cytokines can enable engineered T-cells to eliminate tumor cells. CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains. They have recently shown clinical benefit in patients treated with CD19-directed autologous T-cells. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics. Here, we briefly review early studies, consider strategies to improve the therapeutic potential and safety, and discuss the challenges and future prospects for CAR T-cells in cancer therapy.

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Erratum to: Menthol Inhibits the Proliferation and Motility of Prostate Cancer DU145 Cells

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Evaluation of a weekly speech pathology/dietetic service model for providing supportive care intervention to head and neck cancer patients and their carers during (chemo)radiotherapy

Abstract

Purpose

Dysphagia is a common and debilitating side effect for head and neck cancer (HNC) patients undergoing radiotherapy (RT) with or without chemotherapy ([C]RT) and is associated with nutritional and emotional comorbidities. Emotional sequelae and distress are also known to affect carers of HNC patients. A weekly, joint speech pathology/dietetic (SP/DN) service-delivery model has been employed to manage swallowing/nutritional and associated emotional issues during (C)RT. This study aimed to conduct a service evaluation of the weekly SP/DN clinical model.

Methods

Cross-sectional sampling of core service metrics and perceptions of key stakeholders (70 HNC patients, 30 carers, and 10 clinicians) were collated from the Metro South Radiation Oncology Service in Brisbane, Australia. Data from each source was examined separately and then triangulated.

Results

An average of 28 patients (SD = 5.54) attended SP/DN appointments per week, with 58 % reporting swallowing and/or nutritional issues. Distress was reported by 27 % of patients and 30 % of carers. Clinicians felt able to adequately identify and manage swallowing and nutrition 90 % of the time but only 10 % of the time for distress. Seventy-six percent of scheduled SP/DN sessions were perceived as necessary by either patients, clinicians or both.

Conclusions

Findings demonstrated a third of patients and their carers had a high level of distress during HNC [C]RT, supporting need for the provision of a weekly SP/DN service in a select cohort. However, the routine weekly SP/DN assessment model for all patients undergoing HNC treatment demonstrates the potential for over-servicing. Alternative service-delivery models warrant further evaluation.

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Poor chemotherapy-induced nausea and vomiting control in children receiving intermediate or high dose methotrexate

Abstract

Purpose

Chemotherapy emetogenicity is the most important known determinant of chemotherapy-induced vomiting (CIV) in children. However, direct evidence regarding the emetogenic potential of chemotherapeutic agents in children is limited. This study describes the prevalence of complete control of acute and delayed phase chemotherapy-induced nausea and vomiting (CINV) in children receiving methotrexate. The prevalence of anticipatory CINV is described, and risk factors for CINV are explored.

Methods

English-speaking children (4 to 18 years) receiving intermediate-dose (ID-MTX: >1 to <12 g/m²/dose) or high-dose methotrexate (HD-MTX: ≥12 g/m²/dose) participated in this prospective study. Emetic episodes, nausea severity, and antiemetic administration were documented for 24 h from the start of the methotrexate infusion (acute phase) and for up to a further 168 h (delayed phase). CINV prophylaxis was provided at the discretion of the treating physician. Anticipatory CINV was assessed in the 24 h preceding chemotherapy. Complete CINV control was defined as no emetic episodes and no nausea.

Results

Thirty children (mean age, 11.8 ± 4 years; ID-MTX, 20; HD-MTX, 10) completed the study. CINV prophylaxis included the following: ondansetron/granisetron plus dexamethasone or nabilone. Few patients experienced complete CINV control (ID-MTX: acute phase 20 %, delayed phase 5 %; HD-MTX: acute phase 0 %, delayed phase 30 %). Complete emesis control was higher (ID-MTX: acute phase 70 %, delayed phase 50 %; HD-MTX: acute phase 70 %, delayed phase 60 %). Anticipatory CINV was reported by 6/28 patients (21 %). Patient age, sex, and history of motion sickness were not significant predictors of CINV.

Conclusions

The poor complete CINV control rate in children receiving methotrexate confirms the classification of HD-MTX as highly emetogenic chemotherapy (HEC) and suggests that ID-MTX be reclassified as HEC.

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Effect of minimal enteral feeding on recovery in a methotrexate-induced gastrointestinal mucositis rat model

Abstract

Purpose

Patients suffering from gastrointestinal mucositis often receive parenteral nutrition as nutritional support. However, the absence of enteral nutrition might not be beneficial for the intestine. We aimed to determine the feasibility of minimal enteral feeding (MEF) administration in a methotrexate (MTX)-induced mucositis rat model and thereby determine the effect of MEF on recovery.

Methods

Male Wistar rats were attached to swivel systems from day 1 to 5 after 45 mg/kg MTX IV injection. The MTX group continued ad libitum feeding, and the MTX + MEF group continued ad libitum feeding and received from day 1 to 5 continuously MEF. MEF consisted of 20 % of their normal caloric intake. We measured body weight, intake, and plasma citrulline. At day 10, the rats were terminated and villus and crypt length were measured.

Results

The administration of MEF caused no increased severity of mucositis phenotype, with comparable caloric intake, body weight, and plasma citrulline during mucositis. The recovery of plasma citrulline levels was not different between both groups. At day 7 and 8, the MTX + MEF group gained significantly more weight (p < 0.05 and p < 0.01, respectively), and at day 8 and 9 the total caloric intake was significantly increased (p < 0.01 and p < 0.05, respectively) compared to the MTX group. At day 10, the rats from the MTX + MEF group showed a significant increase in jejunal villus length compared to the MTX group (p < 0.05).

Conclusions

This is the first study in which the feasibility of MEF administration during chemotherapy-induced mucositis was determined. This study indicates that MEF administration is feasible during mucositis and suggests that MEF accelerates recovery after MTX-induced mucositis.

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MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy

Abstract

Purpose

Previous pilot data suggested that venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy. The purpose of this randomized, placebo-controlled, double-blinded pilot study was to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity.

Methods

Fifty patients, scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stages II–III (67 %) or stage IV (33 %) colon cancer, were randomized to receive venlafaxine extended release (37.5 mg) or placebo, twice daily, through their last dose of oxaliplatin and then titrated off. Neurotoxicity was evaluated via several patient- and physician-reported measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) instrument.

Results

Baseline patient characteristics were equivalent for the two arms, with a median age of 60 years. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin-specific neuropathy scale and by acute neuropathy measures of throat discomfort and discomfort swallowing cold liquids, the latter only for the first two oxaliplatin doses. These trends were outweighed by a lack of any such trends in all other measurements including the following: (1) the CIPN20 sensory subscale (P = 0.55, primary endpoint), physician-completed NCI CTCAE assessment, or cumulative administered oxaliplatin doses (median 716 vs 631 mg for placebo and venlafaxine, respectively, P = 0.34).

Conclusions

The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting.

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Pegfilgrastim administration after 24 or 72 or 96 h to allow dose-dense anthracycline- and taxane-based chemotherapy in breast cancer patients: a single-center experience within the GIM2 randomized phase III trial

Abstract

Purpose

To evaluate the safest timing of pegfilgrastim administration in dose-dense anthracycline- and taxane-based chemotherapy, three different cohorts of patients enrolled in the Gruppo Italiano Mammella (GIM) 2 study and treated at the coordinating center received pegfilgrastim 24 h (cohort A) or 72 h (cohort B) or 96 h (cohort C) after chemotherapy.

Methods

A total of 41 patients were included. The safety of pegfilgrastim administration in terms of occurrence of early and late leukocytosis and the behavior of white blood cells (WBC) counts in the three cohorts across all chemotherapy cycles were evaluated. Anthracycline and taxane cycles were analyzed separately.

Results

The occurrence of early leukocytosis was a more common event in patients in cohort A in both anthracycline and taxane cycles (75 and 66.7 %) as compared to cohort B (50 and 60 %) and cohort C (66.7 and 33.3 %). More patients in cohort C developed late leukocytosis in both anthracycline and taxane cycles (50 and 100 %) as compared to cohort A (0 and 66.7 %) and cohort B (35.7 and 86.7 %). Patients in cohort A experienced the highest median value of WBC count 24 h after pegfilgrastim administration in both anthracycline and taxane cycles (61.2 × 10³/μl and 67.8 × 10³/μl). Patients in cohort C experienced the highest median value of WBC count at day 13 in both anthracycline and taxane cycles (19.4 × 10³/μl and 24.2 × 10³/μl).

Conclusions

For the prevention of leukocytosis, the safest timing of pegfilgrastim administration based on WBC count in dose-dense anthracycline- and taxane-based regimens seems to be 72 h after chemotherapy.

Trial registration

This study is registered with http://ift.tt/1QtJulp.

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Reversal of muscle atrophy by Zhimu and Huangbai herb pair via activation of IGF-1/Akt and autophagy signal in cancer cachexia

Abstract

Purpose

Muscle atrophy is the prominent clinical feature of cancer-induced cachexia. Zhimu and Huangbai herb pair (ZBHP) has been used since ancient China times and have been phytochemically investigated for constituents that might cause anti-cancer, diabetes, and their complication. In this study, the effects and mechanisms of ZBHP on reversal of muscle atrophy were explored.

Methods

C57BL/6 mice implanted with colon-26 adenocarcinoma were chosen to develop cancer cachexia for evaluating the effects of ZBHP on reversal of muscle atrophy. The body weight, survival time, inflammatory cytokines, and pathological changes of muscle were monitored. In addition, IGF-1/Akt and autophagy pathway members were analyzed to interpret the mechanism of drug response.

Results

The function and morphology of skeletal muscle in cachexia model were significantly disturbed, and the survival time was shortened. Consistently, inflammatory cytokines and muscle atrophy-related atrogin-1, MuRF1, and FOXO3 were significantly increased, and IGF-1/Akt and autophagy signal pathways were depressed. Treatment with ZBHP significantly alleviated tumor-free body weight reduction and cachexia-induced changes in cytokines and prolonged survival. ZBHP treatment not only inhibited the muscle atrophy-related genes but also activated the IGF-1/Akt and autophagy signal pathways to facilitate the protein synthesis.

Conclusions

The results revealed that ZBHP treatment could inhibit the muscle atrophy induced by cancer cachexia and prolong the survival time, and ZBHP may be of value as a pharmacological alternative in treatment of cancer cachexia.

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Contrast-induced nephropathy in patients with active cancer undergoing contrast-enhanced computed tomography

Abstract

Purpose

This study was performed to measure the incidence and identify potential predictors of contrast-induced nephropathy (CIN) in cancer patients without chronic kidney disease and with normal or near-normal baseline serum creatinine measures who underwent contrast-enhanced computed tomography (CECT). Severity of CIN was reported based on the RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal disease) classification of acute kidney injury.

Methods

A retrospective analysis was performed on 820 cancer patients who presented at our emergency department from October 2014 to March 2015. CIN was defined as an increase in creatinine concentration of ≥0.5 mg/dL or ≥25 % above baseline that occurred 48 to 72 h after CECT.

Results

The incidence of CIN was 8.0 %. Serial CT examination [odds ratio (OR) 4.09; 95 % confidence interval (CI) 1.34–12.56], hypotension before the CT scan (OR 3.95; 95 % CI 1.77–8.83), liver cirrhosis (OR 2.82; 95 % CI 1.06–7.55), BUN/creatinine >20 (OR 2.54; 95 % CI 1.44–4.46), and peritoneal carcinomatosis (OR 1.75; 95 % CI 1.01–3.00) were independently associated with CIN. Of 66 CIN patients, 44 met any of the severity criteria of the RIFLE classification. Five of these patients died during hospitalization but only one death was related to renal failure.

Conclusions

Even when the baseline serum creatinine is ≤1.5 mg/dL, a significant portion of cancer patients are still at risk of CIN. Consecutive CECT examinations, hypotension before CT, liver cirrhosis, dehydration, and peritoneal carcinomatosis seem to predispose patients to CIN.

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A new once-a-day fentanyl citrate patch (Fentos® Tape) could be a new treatment option in patients with end-of-dose failure using a 72-h transdermal fentanyl matrix patch

Abstract

Purpose

The recommended dosing interval for transdermal fentanyl is every 72 h. However, some patients will have "end-of-dose failure," which may be seen as an increase of episodes of severe pain flares at the third day after application of the patch. A new once-a-day fentanyl patch was developed in Japan since 2010. This study aimed to assess the efficacy of the once-a-day fentanyl citrate patch for patients with cancer-related pain receiving the 72-h transdermal fentanyl not lasting 72 h.

Methods

We performed a cross-sectional retrospective analysis of 445 inpatients with the 72-h transdermal fentanyl at Higashi Sapporo Hospital. We could switch to the once-a-day fentanyl citrate patch if patients reported inadequate pain relief beyond 48 h after application of the 72-h transdermal fentanyl. Patients recorded baseline scores for background pain intensity (PI) and the frequency of use of daily rescue medication for breakthrough cancer pain (BTcP).

Results

Of all patients, 10.1 % showed the increase in PI of 30 % or more baseline PI on the third day after application of the 72-h transdermal fentanyl. Of patients, 84.4 % were converted from equivalent dose of the 72-h transdermal fentanyl to the once-a-day fentanyl citrate patch. On the third day after switching, 60.5 % of patients showed a reduction of more than 30 % from baseline PI. Switching to the once-a-day fentanyl citrate patch significantly reduced the mean frequency of daily rescue dose for BTcP.

Conclusions

A once-a-day fentanyl citrate patch provided stable pain control. Its use may be considered as the dominant strategy for patients receiving a 72-h transdermal fentanyl not lasting 72 h.

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Breast cancer-related lymphedema after axillary lymph node dissection: does early postoperative prediction model work?

Abstract

Purpose

Early detection and timely intervention demonstrate the greatest promise of reducing the incidence of late-stage lymphedema in breast cancer patients undergoing axillary lymph node dissection (ALND). A nomogram was developed for predicting the risk of lymphedema (LE) in patients with ALND. This study's aim was to test the early postoperative prediction model for the diagnosis of clinical and subclinical LE after ALND.

Methods

Patients requiring ALND were identified preoperatively through our LE program database. Measurements using metered tape with bioimpedance spectroscopy (L-Dex® U400) were obtained preoperatively (n = 180) and at 3–6-month intervals postoperatively. The 5-year probability of LE after ALND was calculated using the Cleveland Clinic Risk Calculator. The discrimination of the nomogram was assessed by calculating the area under (AUC) the receiver operating characteristic curve.

Results

LE was present in 36.1 % (n = 65) of 180 patients with ALND. Of these 65 patients, 22 (12.2 %) had clinical LE and 43 (23.9 %) had subclinical LE. Statistical analyses showed significant differences in BMI and receipt of radiotherapy between patients with and without LE (p = 0.03 and p = 0.01, respectively). AUC was 0.601, 0.614, and 0.600 for the nomogram using any LE, clinical LE, and subclinical LE patients, respectively.

Conclusions

The recently created prediction model for the diagnosis of LE in ALND is not accurate in predicting who will develop clinical or subclinical LE. Periodic monitoring of women with ALND is the most effective method to aid in reducing clinical LE incidence through early detection and timely intervention of LE.

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Patient housing barriers to hematopoietic cell transplantation: results from a mixed-methods study of transplant center social workers

Abstract

Purpose

Hematopoietic cell transplantation (HCT) is performed in select centers in the United States (U.S.), and patients are often required to temporarily relocate to receive care. The purpose of this study was to identify housing barriers impacting access to HCT and potential solutions.

Methods

A mixed-methods primary study of HCT social workers was conducted to learn about patient housing challenges and solutions in place that help address those barriers. Three telephone focus groups were conducted with adult and pediatric transplant social workers (n = 15). Focus group results informed the design of a national survey. The online survey was e-mailed to a primary social worker contact at 133 adult and pediatric transplant centers in the U.S. Transplant centers were classified based on the patient population cared for by the social worker.

Results

The survey response rate was 49 %. Among adult programs (n = 45), 93 % of centers had patients that had to relocate closer to the transplant center to proceed with HCT. The most common type of housing option offered was discounted hotel rates. Among pediatric programs (n = 20), 90 % of centers had patients that had to relocate closer to the transplant center to proceed with HCT. Ronald McDonald House was the most common option available.

Conclusions

This study is the first to explore housing challenges faced by patients undergoing HCT in the U.S. from the perspective of social workers and to highlight solutions that centers use. Transplant centers will benefit from this knowledge by learning about options for addressing housing barriers for their patients.

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Risk and management of venous thromboembolisms in bevacizumab-treated metastatic colorectal cancer patients

Abstract

Purpose

Bevacizumab may potentiate the risk of venous thromboembolisms (VTEs) in cancer patients, who are already predisposed to pro-thrombotic states. We aimed to characterize the incidence of VTEs in a population-based cohort of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, describe patient and treatment factors associated with VTEs, and examine how VTEs are managed.

Methods

Patients diagnosed with mCRC from 2006 to 2009 and offered bevacizumab were included. Descriptive statistics were used to describe VTE occurrences and management. Univariate and multivariate regression models were constructed to explore associations between clinical factors and VTEs.

Results

We identified 541 mCRC patients: 27 never started bevacizumab and 15 were lost to follow-up. Of the 499 evaluable patients, median age was 61, 59.3 % were men, 88.1 % had ECOG 0/1, and 5.2 % reported previous VTEs. Mean number of bevacizumab doses was 13.3 cycles. After receiving bevacizumab, 81 patients developed 93 cases of VTEs, with 9 patients experiencing >1 event. Individuals who experienced VTEs were more likely to have had pre-existing cardiovascular disease (OR 2.259, p = 0.0245), resection of primary cancer (OR 3.262, p = 0.0269), pre-chemotherapy platelet count ≥350,000/μL (OR 2.295, p = 0.0293), and received >12 bevacizumab cycles (OR 2.172, p = 0.0158). Use of bevacizumab varied after occurrence of VTE where it was discontinued in 34.4 %, continued in 34.4 %, and temporarily held in 1.1 %.

Conclusions

VTE risk can be high, especially in patients with specific pre-treatment risk factors as well as in those who received more bevacizumab, suggesting a potential dose-related effect. Management of bevacizumab-related VTEs was variable.

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Randomized study of sequential cisplatin-topotecan/carboplatin-paclitaxel versus carboplatin-paclitaxel: effects on quality of life

Abstract

Background

A recent phase III trial compared the efficacy of cisplatin-topotecan (a topoisomerase I inhibitor) followed by carboplatin-paclitaxel (Arm 1) versus paclitaxel-carboplatin (Arm 2) in women with newly diagnosed stage IIB or greater ovarian cancer. There was a significantly lower response rate in the experimental arm compared to standard treatment, and less likelihood of normalized CA125 within the first 3 months. At 43 months follow-up, there were no significant group differences in progression-free survival. There were also significantly more side effects in the experimental arm.

Methods

The current study examined quality of life (QoL) endpoints using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the ovarian cancer module, QLQ-OV28, administered prior to randomization, at day 1 of treatment cycles 3, 5, and 7, at completion of the last cycle, and at 3 and 6 months following completion of chemotherapy.

Results

Global QoL, physical symptoms, fatigue, and role, emotional, cognitive and social function (all from the EORTC QLQ-C30) significantly improved in both treatment arms, with no significant between-arm differences. Between-group differences in pain, insomnia, and peripheral neuropathy reported while on treatment did not differ at follow-up. Nausea and vomiting improved more with standard treatment both during and after treatment. Body image significantly differed between the groups only at cycle 5 (more deterioration in Arm 2) but group differences disappeared at follow-up. A stratified analysis of global QoL by debulking surgery status found no greater effect indicating that overall improvements in QoL were unrelated to surgical recovery.

Conclusions

There was no significant QoL advantage of cisplatin-topotecan. This finding, combined with no progression-free survival conferred by this combination, reaffirms carboplatin-paclitaxel as the standard of care for women with newly diagnosed ovarian cancer.

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How to improve the prevention of chemotherapy-induced nausea and vomiting? The French NAVI study

Abstract

Purpose

Chemotherapy-induced nausea and vomiting (CINV) still remain frequent. The procedure for announcing the diagnosis (PAD) was an emblematic measure of the first French Plan Cancer aiming at providing patients with time to listen, information after cancer diagnosis, and discussion on treatments and their side effects. We aimed at assessing the risk factors of CINV, focusing on patients' satisfaction with the PAD.

Methods

This prospective multicentre study assessed the frequency and intensity of CINV among chemonaïve patients during the first cycle of treatment. CINV was defined by ≥1 emetic episode or reported nausea intensity ≥3 on a 0–10 scale. Multivariate analysis was used to identify factors related to global CINV onset including satisfaction with the PAD (satisfaction score ≥the median on a 0–10 scale).

Results

Data from 291 patients (women, 85.2 %; mean age, 57 years) were analyzed. Most patients (69.4 %) received highly emetogenic chemotherapy regimens and 77.7 % received antiemetic drugs consistent with international guidelines. Acute, delayed and overall CINV were experienced by 40.4, 34.8 and 52.4 % of patients, respectively. Sixty-seven per cent of patients were satisfied with the PAD. No relation was noted between PAD satisfaction and CINV onset. The nausea and vomiting dimension of the QLQ-C30 questionnaire before chemotherapy (OR 3.62), motion sickness history (OR 2.73), highly emetogenic CT (OR 2.73), anxiety (OR 1.99) and younger age (OR 1.96) were independent predictive factors.

Conclusions

Although patients were mostly satisfied with the PAD, half of them experienced CINV. A state of anxiety could be identified during the PAD to be managed.

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Beyond current aprepitant evidence: room for improvement on dose selection and chemotherapy-induced nausea and vomiting risk factors

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The cultural constructs of cancer-related fatigue among American Indian cancer survivors

Abstract

Purpose

Cancer-related fatigue (CRF) is a common symptom experienced by cancer survivors. Persistent fatigue can last years after cancer treatment. CRF's origin is unknown, and there are no validated treatments. Cultural constructs (definitions, meaning, and explanations) may vary the presentation and treatment choices related to fatigue. Identifying and categorizing CRF terms and experiences among racial, ethnic, and non-English speaking groups may provide a fuller understanding of CRF to guide tailoring of interventions. We report on the cultural constructs of CRF as reported by American Indian cancer survivors.

Methods

A study of Southwest American Indians collected qualitative data on cancer survivors' experiences of fatigue. Focus groups (n = 132) at urban clinics and rural reservation sites in the Southwest collected qualitative data on cancer survivor experiences with fatigue. The sessions were audiotaped and transcribed verbatim. During analysis, common themes were coded and formed into categories following Grounded Theory analytical procedures. Relationships between categories were examined.

Results

CRF was described by survivors as an entity that comes into the brain, "drains life" from the body, and creates long-lasting suffering, pain, and stigma. We review the cultural constructs of fatigue and CRF's relationship to "being out of balance."

Conclusions

There is a need for culturally appropriate education concerning fatigue, techniques for reducing fatigue, and support for American Indian cancer survivors and other vulnerable populations.

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Sixty-minute infusion rituximab protocol allows for safe and efficient workflow

Abstract

Purpose

Rituximab is a chimeric monoclonal antibody approved to treat B cell non-Hodgkin's lymphoma (NHL). Infusion reactions among NHL patients are common during the first exposure but decrease with subsequent infusions. We sought to assess the safety and feasibility of a rituximab rapid infusion protocol in the outpatient treatment area of a comprehensive cancer center.

Patients and methods

Patients with indolent and intermediate B cell NHL were invited to enroll in this prospective, single-institution study if they had received the first dose of rituximab according to the manufacturer-labeled standard titration schedule without grade >2 infusion reaction. The subsequent infusion proceeded without the use of steroid premedication at 100 mg/h administered over 15 min, with the remaining dose given over 45 min. Time savings between rapid infusion and standard titration were calculated.

Results

Fifty patients received 60-min rituximab infusions during the second drug administration. No infusion-related reactions of any grade were observed with the rapid infusion protocol (0 %, one-sided 97.5 % CI 0–7.1 %). The mean time for the rapid rituximab infusion was 62.4 min (95 % CI 61.2–63.6). When compared to the standard second dose infusion recommendation, a mean time of 94.2 min (95 % 90–98.4) was saved with rapid infusion. Nursing surveys demonstrated 100 % satisfaction with the rapid infusion protocol.

Conclusions

Subsequent rituximab infusions can be safely administered over 60 min and without steroid premedication in an experienced outpatient infusion center when patients are appropriately screened. The faster infusions can reduce resource utilization and increase nursing satisfaction.

Trial Registration

NCT01206777

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Phase II evaluation of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes

Abstract

Purpose

Hot flashes are a significant source of symptom burden that negatively impacts quality of life (QOL). For women who have contraindications to, or are unwilling to consider, estrogens or antidepressants for bothersome hot flashes, there are limited effective pharmacologic or complementary and alternative medicines.

Methods

This single-arm phase II trial studied the efficacy of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes. Eligible women were required to have reported ≥14 hot flashes per week for ≥1 month. The patients were treated with SAMe at a dose of 400 mg twice daily to evaluate whether a reduction in hot flash score appeared to be better than the historical placebo response of approximately 25 %. The women kept a daily hot flash diary during a baseline week and then daily during weeks 2–7. The primary endpoint was the change from baseline to week 7 in hot flash score and hot flash frequency. Secondary endpoints included toxicity analyses and the effect of SAMe on QOL.

Results

From October 28, 2010 to January 30, 2012, 43 women were treated with SAMe. The decrease in mean percent of baseline hot flash score and frequency was 35.4 and 32.6 %, respectively. When compared to the historical placebo response of 25 %, the effect of SAMe on hot flash score was not statistically significant (p = 0.09). Treatment was well tolerated with expected grade 1/2 gastrointestinal toxicity and no negative effect on QOL.

Conclusions

The use of SAMe does not appear to significantly reduce hot flashes more than would be expected with a placebo.

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Venous access: the patient experience

Abstract

Introduction

The evolution of venous access via peripheral cannulation, particularly in relation to the risks and the benefits of this procedure, is reported widely in the literature. However, there is limited research specific to the patient experience of undergoing venous access.

Aim

The intent of this qualitative study was to understand patients' experience of venous access, with the aim of bringing forth their voices about the experiences of repeated venous access/cannulation attempts.

Methodology

This qualitative study used a hermeneutic phenomenological approach to explore the experiences of 15 participants in two rural oncology units in Australia. The participants had experienced repeated peripheral cannulation in order to receive chemotherapy. Study participants were asked to describe what it was like for them to be repeatedly cannulated. Data were collected via audiotaped individual interviews, the participants' stories were transcribed and analysed thematically.

Outcomes

Themes emerged from the participants' stories that provided insights into their perceptions of the experience of being cannulated and the decision-making processes regarding how and where the procedure occurred. The findings suggest that a holistic approach to care was often missing causing the participants to feel vulnerable. Gaining insight into their experiences led to a greater understanding of the impact of this procedure on patients and the need to improve care through encouraging more collaborative decision-making processes between clinicians and patients.

Conclusion

The implications for policy and practice focus on improving patient outcomes via procedural governance and education, with the intent of translating the findings from this research into evidence-based practice.

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Phase II randomized, controlled trial of 1 day versus 3 days of dexamethasone combined with palonosetron and aprepitant to prevent nausea and vomiting in Japanese breast cancer patients receiving anthracycline-based chemotherapy

Abstract

Purpose

Dexamethasone, plus a 5-HT3 receptor antagonist and an NK-1 receptor antagonist are recommended for controlling the chemotherapy-induced nausea and vomiting (CINV) of highly emetogenic chemotherapy. Several days of dexamethasone are effective for CINV; however, dexamethasone also has side effects. The purpose of this trial was to investigate whether the use of a second-generation 5-HT3 receptor antagonist and an NK-1 receptor antagonist could allow a reduced dose of dexamethasone for breast cancer patients receiving highly emetogenic chemotherapy.

Methods

Eighty breast cancer patients who received an anthracycline-cyclophosphamide combination regimen were enrolled. The patients were randomized to arm A (dexamethasone days 1–3) and arm B (dexamethasone day 1). The primary endpoint was complete response (CR) (no emetic episodes and no rescue medication) during the overall phase (days 1–5). The secondary endpoints were the CR during the delayed phase (days 2–5), complete control (CC) (no emetic episodes, no rescue medication, and no more than mild nausea) during the overall phase, and the safety of this antiemetic therapy.

Results

There were no significant differences in the rates of CR and CC between arm A and B as follows: CR overall phase—arm A: 82.9 %, 90 % confidence interval [CI] 71.3–90.5 % vs arm B: 82.1 %, 90 % CI 70.0–90.0 %; p = 1.00; CR delayed phase—arm A: 87.8 %, 90 % CI 77.0–93.9 % vs arm B: 94.9 %, 90 % CI 85.6–98.3 %; p = 0.43; CC overall phase—arm A: 48.8 %, 90 % CI 36.4–61.3 % vs arm B: 61.5 %, 90 % CI 48.4–73.2 %; p = 0.27. There were very few adverse events and no severe adverse events associated with this antiemetic therapy.

Conclusions

The results suggest that the antiemetic effect provided by dexamethasone administered for 3 days can be obtained by dexamethasone administered for 1 day.

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Growth Arrest Line Mimicking Lymphoma Involvement: The Findings of 99m Tc-MDP Bone SPECT/CT and Serial Bone Scan in a Child with Non-Hodgkin’s Lymphoma

Abstract

Growth arrest lines appear as dense sclerotic lines parallel to the growth plate of long bones on radiography. We describe the case of a 9-year-old female with growth arrest lines initially masquerading as lymphoma involvement on ^99mTc-MDP bone scintigraphy who had been treated with chemotherapy for non-Hodgkin's lymphoma about 3 years previously. Subsequent regional bone SPECT/CT clearly diagnosed the growth arrest lines, and retrograde review of previous bone scintigraphy demonstrated line migration in this patient. Growth arrest lines should be considered a possible diagnosis on bone scintigraphy, especially in the surveillance of children who have experienced severe childhood infections, malnutrition, immobilization, or treatment with immunosuppressive or chemotherapeutic drugs that may inhibit bone growth.

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Sunitinib activates Axl signaling in renal cell cancer

ABSTRACT

Mass spectrometry-based phosphoproteomics provides a unique unbiased approach to evaluate signaling network in cancer cells. The tyrosine kinase inhibitor sunitinib is registered as treatment for patients with renal cell cancer (RCC). We investigated the effect of sunitinib on tyrosine phosphorylation in RCC tumor cells to get more insight in its mechanism of action and thereby to find potential leads for combination treatment strategies. Sunitinib inhibitory concentrations of proliferation (IC50) of 786-O, 769-p and A498 RCC cells were determined by MTT-assays. Global tyrosine phosphorylation was measured by LC-MS/MS after immunoprecipitation with the antiphosphotyrosine antibody p-TYR-100. Phosphoproteomic profiling of 786-O cells yielded 1519 phosphopeptides, corresponding to 675 unique proteins including 57 different phosphorylated protein kinases. Compared to control, incubation with sunitinib at its IC50 of 2µM resulted in downregulation of 86 phosphopeptides including CDK5, DYRK3, DYRK4, G6PD, PKM and LDH-A, while 94 phosphopeptides including Axl, FAK, EPHA2 and p38α were upregulated. Axl- (y702), FAK- (y576) and p38α (y182) upregulation was confirmed by Western Blot in 786-O and A498 cells. Subsequent proliferation assays revealed that inhibition of Axl with a small molecule inhibitor (R428) sensitized 786-O RCC cells and immortalized endothelial cells to sunitinib up to 3 fold. In conclusion, incubation with sunitinib of RCC cells causes significant upregulation of multiple phosphopeptides including Axl. Simultaneous inhibition of Axl improves the antitumor activity of sunitinib. We envision that evaluation of phosphoproteomic changes by TKI treatment enables identification of new targets for combination treatment strategies. This article is protected by copyright. All rights reserved.

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The proportion cured of patients diagnosed with stage III-IV cutaneous malignant melanoma in Sweden 1990-2007: A population-based study

Abstract

The survival in cutaneous malignant melanoma (CMM) is highly dependent on the stage of the disease. Stage III-IV CMM patients are at high risk of relapse with a heterogeneous outcome, but not all experience excess mortality due to their disease. This group is referred to as the cure proportion representing the proportion of patients who experience the same mortality rate as the general population. The aim of this study was to estimate the cure proportion of patients diagnosed with stage III-IV CMM in Sweden. From the population-based Swedish Melanoma Register, we included 856 patients diagnosed with primary stage III-IV CMM, 1990-2007, followed-up through 2013. We used flexible parametric cure models to estimate cure proportions and median survival times (MSTs) of uncured by sex, age, tumor site, ulceration status (in stage III patients) and clinical stage. The standardized (over sex, age and site) cure proportion was lower in stage IV CMMs (0.15, 95% CI 0.09-0.22) than non-ulcerated stage III CMMs (0.48, 95% CI 0.41-0.55) with a statistically significant difference of 0.33 (95% CI=0.24-0.41). Ulcerated stage III CMMs had a cure proportion of 0.27 (95% CI 0.21-0.32) with a statistically significant difference compared to non-ulcerated stage III CMMs (difference 0.21; 95% CI=0.13-0.30). The standardized MST of uncured was approximately 9-10 months longer for non-ulcerated vs. ulcerated stage III CMMs. We could demonstrate a significantly better outcome in patients diagnosed with non-ulcerated stage III CMMs compared to ulcerated stage III CMMs and stage IV disease after adjusting for age, sex and tumor site. This article is protected by copyright. All rights reserved.

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Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of Interleukin-6 signaling pathway

Abstract

Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell surface molecule that can mediate homophilic adhesion and promote neurite outgrowth from cultured dorsal root ganglion (DRG) neurons. Interestingly, Ninj1 overexpressed in human cancer; however its role in metastasis is not clear. This study showed that inhibition of Ninj1 promotes lung cancer metastasis through IL-6/STAT3 signaling. Ninj1 levels were relatively low in highly motile lung cancer cells. While inhibition of Ninj1 enhanced cell migration in lung cancer cells, overexpression of Ninj1 significantly suppressed it. We found that inhibition of Ninj1 significantly increased expression and secretion of IL-6 in A549 cells. We also found that inhibition of IL-6 decreased intercellular adhesion molecule 1 (ICAM-1) expression. In addition, inhibition of Ninj1 significantly increased cell motility and invasiveness of lung cancer cells. In an in vivo model, we found that Ninj1 suppression did not affect tumor growth but induced significant increase in incidence of lung metastasis, and sizes and number of tumor nodules. Taken together, our data clearly demonstrate that Ninj1 suppresses migration, invasion, and metastasis of lung cancer via inhibition of the IL-6 signaling pathway in vitro and in vivo. This article is protected by copyright. All rights reserved.

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Protein Z: A putative novel biomarker for early detection of ovarian cancer

Abstract

Ovarian cancer (OC) has the highest mortality of all gynaecological cancers. Early diagnosis offers an approach to achieving better outcomes. We conducted a blinded-evaluation of prospectively collected preclinical serum from participants in the multimodal group of the United Kingdom Collaborative Trial of Ovarian Cancer Screening. Using isobaric tags (iTRAQ) we identified 90 proteins differentially expressed between OC cases and controls. A second targeted mass spectrometry analysis of twenty of these candidates identified Protein Z as a potential early detection biomarker for OC. This was further validated by ELISA analysis in 482 serial serum samples, from 80 individuals, 49 OC cases and 31 controls, spanning up to 7 years prior to diagnosis. Protein Z was significantly down-regulated up to 2 years pre-diagnosis (p = 0.000000411) in 8 of 19 Type I patients whilst in 5 Type II individuals, it was significantly up-regulated up to 4 years before diagnosis (p=0.01). ROC curve analysis for CA-125 and CA-125 combined with Protein Z showed a statistically significant (p= 0.00033) increase in the AUC from 77% to 81% for Type I and a statistically significant (p= 0.00003) increase in the AUC from 76% to 82% for Type II. Protein Z is a novel independent early detection biomarker for Type I and Type II ovarian cancer; which can discriminate between both types. Protein Z also adds to CA-125 and potentially the Risk of Ovarian Cancer algorithm in the detection of both subtypes. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc.

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Clinical significance of circulating plasma DNA in gastric cancer

Abstract

With the progression of molecular techniques, the detection of circulating plasma DNA (cpDNA) is clinically feasible. However, the role of the cpDNA levels in gastric cancer is not well understood. This study assessed the mutational profile in primary tumors and clarified the clinical utility of quantitative and qualitative cpDNA alterations in 277 patients with advanced gastric cancer. The concentrations of cpDNA were measured by TaqMan qPCR, and 68 mutations in 8 genes were studied for cpDNA mutations. The median cpDNA concentrations in patients with stage I, II, and III gastric cancer were 3979, 3390, and 4278 copies/mL, respectively, and increased to 11,380 copies/mL in patients with stage IV gastric cancer (P<0.001). Among the 35 patients harboring cpDNA mutations, stage IV patients (100%) were more likely to display high cpDNA levels than were stage I (33.3%), II (75%), and III patients (66.7%) (P=0.037). Patients displaying high cpDNA levels were more likely to experience peritoneal recurrence and exhibited significantly lower 5-year overall survival rates (39.2% vs. 45.8%, P = 0.039) than did patients displaying low cpDNA levels. Only for late stage (stage III or IV) gastric cancer, patients harboring cpDNA mutations were more likely to experience vascular invasion (20% vs. 2.4%, P=0.036) and exhibited a lower 5-year overall survival rate than did those lacking cpDNA mutations (5.6% vs. 31.5%, P=0.028). High cpDNA levels are associated with peritoneal recurrence and poor prognosis in patients with advanced gastric cancer; harboring cpDNA mutations is associated with poor prognosis among patients with late stage gastric cancer. This article is protected by copyright. All rights reserved.

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Use of denosumab in a dialysis patient with bone metastases from breast cancer and hepatorenal polycystic disease: a case report.

Cancer patients with severe renal dysfunction represent a challenge for the physician. This is the first case report on the use of denosumab in a dialysis patient with bone metastases. We present the clinical case of a 45-year-old woman who had hepatorenal polycystic disease, diagnosed during childhood, and stage IV chronic kidney failure at the time of breast cancer diagnosis. Three years after surgery plus adjuvant hormonal therapy she suffered a further worsening of renal function, requiring dialysis, and very advanced bone metastasis in the hip with severe pain. As pamidronate was the only bone agent available in the center, she received it for 4 months (before a dialysis session), during which time the bone metastases stabilized. In March 2014, the patient switched to denosumab (which had become available in the center), and continued with hormone therapy. Seven months after denosumab initiation, the patient had almost complete pain relief, and the bone metastases exhibited radiological improvement. The tolerability was excellent, without any related adverse event. There were no changes in albumin-adjusted serum calcium, serum phosphorus, and intact parathyroid hormone, except for a transient and mild hypocalcemia at 3 months and an increase in intact parathyroid hormone levels, which required adjustment of vitamin D analog dose. Denosumab can be administered to prevent skeletal-related events in patients with bone metastasis from solid tumors and severely impaired renal function, even in those requiring dialysis. In this particular patient, the safety was good. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Spontaneous regression of tumour and the role of microbial infection - possibilities for cancer treatment.

This review deals with the role of microorganisms in spontaneous regression of a tumour. Spontaneous cancer regression is a phenomenon that has been described for many centuries. One of the most well known methods of inducing spontaneous regression of cancer is the application of Coley's toxin (heat-killed Streptococcus pyogenes and Serratia marcescens), which has been used for the successful treatment of sarcomas, carcinomas, lymphomas, myelomas and melanomas. In clinical practice, the use of Bacillus Calmette-Guerin vaccine for the treatment of superficial urinary bladder cancer is the most common instance of the application of microorganisms for the treatment of cancer. This review provides further information on other tested bacteria - Clostridium spp., Bifidobacterium spp., Lactobacillus spp. and Salmonella spp. - in this field of study. Among new age methods, bactofection, alternative gene therapy, combination bacteriolytic therapy and bacteria-directed enzyme prodrug therapy are some of the potential cancer treatment modalities that use microorganisms. We have also provided information about the interconnection among microorganisms, immune system response, and the possible mechanisms involved in the spontaneous regression of tumours. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/1hexVwJ. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Increased risk of colorectal cancer in patients diagnosed with breast cancer in women

Publication date: April 2016
Source:Cancer Epidemiology, Volume 41
Author(s): Yunxia Lu, Josefin Segelman, Ann Nordgren, Lina Lindström, Jan Frisell, Anna Martling
BackgroundEpidemiological studies have shown a potential association between sex hormones and colorectal cancer. The risk of colorectal cancer in breast cancer patients who may have been exposed to increased levels of endogenous sex hormones and/or exogenous sex hormones (e.g. anti-hormonal therapy) has not been thoroughly evaluated.MethodsUsing the National Swedish Cancer Register we established a population-based prospective cohort of breast cancer patients in women diagnosed in Sweden between 1961 and 2010. Subsequent colorectal cancers were identified from the same register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95%CIs) were used to estimate the risk of colorectal cancer after a diagnosis of breast cancer. The association between breast cancer therapy and risk of colorectal cancer was evaluated in a subcohort of breast cancer patients treated in Stockholm between 1977 and 2007. Hazard ratios (HRs) and 95%CIs were estimated using Cox regression models.ResultsIn a cohort of 179,733 breast cancer patients in Sweden, 2571 incident cases of colorectal cancer (1008 adenocarcinomas in the proximal colon, 590 in the distal colon and 808 in the rectum) were identified during an average follow-up of 9.68 years. An increased risk of colorectal adenocarcinoma was observed in the breast cancer cohort compared with that in the general population (SIR=1.59, 95%CI: 1.53, 1.65). Adenocarcinoma in the proximal colon showed a non-significantly higher SIR (1.72, 95%CI: 1.61, 1.82) compared with the distal colon (1.46, 95%CI: 1.34, 1.58). In the subcohort of 20,171 breast cancers with available treatment data, 299 cases with colorectal cancers were identified. No treatment-dependent risk of colorectal cancer was observed among the breast cancer patients.ConclusionAn increased risk of colorectal adenocarcinoma – especially in the proximal colon – was observed in the breast cancer cohort. Breast cancer treatment did not alter this risk.



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The role of oxidative stress on breast cancer development and therapy

Abstract

Reactive oxygen species (ROS) are produced by both enzymatic and non-enzymatic systems within eukaryotic cells and play important roles in cellular physiology and pathophysiology. Although physiological concentrations are crucial for ensuring cell survival, ROS overproduction is detrimental to cells, and considered key-factors for the development of several diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Cancer cells are usually submitted to higher ROS levels that further stimulate malignant phenotype through stimulus to sustained proliferation, death evasion, angiogenesis, invasiveness, and metastasis. The role of ROS on breast cancer etiology and progression is being progressively elucidated. However, less attention has been given to the development of redox system-targeted strategies for breast cancer therapy. In this review, we address the basic mechanisms of ROS production and scavenging in breast tumor cells, and the emerging possibilities of breast cancer therapies targeting ROS homeostasis.

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Downregulation of the WT 1 gene expression via TMPyP4 stabilization of promoter G-quadruplexes in leukemia cells

Abstract

The WT1 gene is an important oncogene, and its overexpression is considered as an effective target for anticancer therapy. Regulation of its gene transcription is one way for WT1-targeting drug design. Recently, in silico analysis of some oncogene promoters like WT1 showed some guanine-rich regions with the ability to form G-quadruplex structures. Ligands like 5,10,15,20-tetra(N-methyl-4-pyridyl)-porphine (TMPyP4) have predominant effect on G-quadruplex stabilization. The aim of this study was to understand the effect of TMPyP4 on WT1 gene transcription via stabilization of promoter G-quadruplexes. We examined the formation of new G-quadruplex motifs in WT1 promoter in the presence of TMPyP4. In order to understand the nature of its interaction with WT1 promoter quadruplexes, differential pulse voltammetry (DPV), circular dichroism (CD), polyacrylamide gel electrophoresis, electrophoretic mobility shift assay (EMSA), polymerase chain reaction (PCR) stop assays, and quantitative RT-PCR were performed. According to the results, the WT1 promoter can form stable intramolecular parallel G-quadruplexes. In addition, after 48 and 96 h of incubation, 100 μM TMPyP4 reduced the WT1 transcription to 9 and 0.4 %, respectively, compare to control. We report that ligand-mediated stabilization of G-quadruplexes within the WT1 promoter can silence WT1 expression. This study might offer the basis for the reasonable design and improvement of new porphyrin derivatives as effective anti-leukemia agents for cancer therapy.

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Elevated STMN1 promotes tumor growth and invasion in endometrial carcinoma

Abstract

Overexpression of stathmin (STMN1) is closely linked to tumor metastases and poor prognosis in endometrial carcinoma (EC). However, the underlying mechanism is little known. In the present study, we investigated the expression of STMN1 in EC. Subsequently, we assessed the role of STMN1 in EC cell proliferation and migration. Our data show that STMN1 is upregulated in EC, and elevated expression of STMN1 is correlated positively with tumor stage and lymph node metastasis. In vitro, forced expression of STMN1 promoted cell invasion and migration. In contrast, knockdown of STMN1 inhibited cell aggressive behaviors. Moreover, the expression and the activity changes of matrix metalloproteinases (MMP)-2/9 were observed in EC cells after the cells being silenced or overexpression of STMN1. In conclusion, STMN1 is an oncogene and it enhances the growth and invasion of EC possibly by mediating the secretion and activation of MMP2 and MMP9 protein.

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SHh-Gli1 signaling pathway promotes cell survival by mediating baculoviral IAP repeat-containing 3 (BIRC3) gene in pancreatic cancer cells

Abstract

The abnormally activated hedgehog (Hh) signaling pathway is involved in the regulation of proliferation and apoptosis in pancreatic cancer cells, while its exact molecular mechanism is not clear. The purpose of this study was to investigate the regulatory effect of Hh signaling pathway on the transcription of BIRC3 gene and its underlying mechanism in pancreatic cancer cells, as well as the relationship between the Gli1-dependent BIRC3 transcription and cell survival. Firstly, we examined the effect of knockdown or overexpression of Hh on BIRC3 messenger RNA (mRNA) expression by real-time RT-PCR. Then, the regulatory mechanism of Gli1 to BIRC3 gene transcription was investigated by XChIP-PCR and luciferase assays. Finally, the cell survival mediated by the Gli1-dependent BIRC3 transcription was studied by MTT and annexin V-FITC/propidiumiodide (PI) assays. We found that the expression level of BIRC3 mRNA was positively correlated to SHh/Gli1 signaling activation in three pancreatic cancer cell lines. The XChIP-PCR and luciferase assays data showed that the transcription factor Gli1 bound to some enhancers within the promoter regions of BIRC3 gene and promoted gene transcription. The cell proliferation was increased significantly by SHh/Gli1 expression while the apoptotic rate was reduced under the same condition. Moreover, BIRC3 knockdown inhibited cell proliferation and survival induced by SHh overexpression. Our study reveals that Gli1 promoted transcription of BIRC3 gene via cis-acting elements and the SHh-Gli1 signaling pathway maintained cell survival partially through this Gli1-dependent BIRC3 model in pancreatic cancer cells.

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Curcumin analogue, A13, exhibits anti-leukemia effect via inhibiting STAT3

Abstract

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) was reported in some leukemia, and inhibition of STAT3 can be the strategy for the leukemia treatment in clinic. In this study, we tested the anti-tumor effect of compound A13, a water-soluble analogue of curcumin, in vitro and in vivo. Herein, we show that A13 was able to reduce the viability of mastocytoma (P815 cells) and reticulum cell sarcoma (A20 cells) as measured by MTS assay. This effect was accompanied by a marked increase in the proportion of apoptotic cells as measured by flow cytometry. Furthermore, Western blot analysis suggested that the anti-leukemia effect of A13 was realized via STAT3 inhibition. In addition, systemic treatment with A13 in the A20-bearing mice for 60 days resulted in a significant improvement of survival rate and marked reduction of liver metastasis. In summary, our data show that the A13 treatment could effectively be applied to acute leukemia via inhibiting STAT3 signaling pathway.

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MiR-608 rs4919510 is associated with prognosis of hepatocellular carcinoma

Abstract

Single nucleotide polymorphisms (SNPs) within microRNAs (miRNAs) are considered potential markers for risk and prognosis of various cancers. In the current study, we aimed to determine whether miR-608 rs4919510 affected hepatocellular carcinoma (HCC) prognosis. We genotyped rs4919510 using DNA from blood samples of 362 HCC patients receiving surgical resection of HCC tumor. Associations between rs4919510 and overall survival (OS) and demographic characteristics and clinical features were estimated using the Cox proportional hazards model. Results showed that HCC patients who carried the rs4919510 CC genotype had a significantly longer OS compared to those who carried the GG genotype (P = 0.013, hazard ratio [HR] = 0.600, 95 % confidence interval [CI] 0.402–0.897) and the CG + GG genotype (P = 0.033, HR = 0.681, 95 % CI 0.479–0.970) in univariate analysis. Similar results were obtained in multivariate analysis. Further stratification analysis indicated that rs4919510 was significantly associated with OS in patients who were satisfied with one of the following criteria: male gender, HbsAg-positive, α-fetoprotein (AFP)-positive, tumor size >5 cm, cirrhosis, solitary tumor, I + II pTNM stage, or no tumor capsule. Finally, a significantly higher frequency of rs4919510 CC genotype was observed in patients with cirrhosis (22.9 %, 55/240) than those without cirrhosis (14.0 %, 17/121) (P = 0.047). In conclusion, our results illustrated the potential role of miR-608 rs4919510 as a prognostic marker for HCC patients undergoing surgical resection of the tumor.

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SUSD2 is frequently downregulated and functions as a tumor suppressor in RCC and lung cancer

Abstract

Sushi domain containing 2 (SUSD2) is type I membrane protein containing domains inherent to adhesion molecules. There have been few reported studies on SUSD2, and they have mainly focused on breast cancer, colon cancer, and HeLa cells. However, the expression and function of SUSD2 in other cancers remain unclear. In the present study, we conducted an integrated bioinformatics analysis based on the array data from the GEO database and found a significant downregulation of SUSD2 in renal cell carcinoma (RCC) and lung cancer. Western blotting and quantitative RT-PCR (qRT-PCR) confirmed that SUSD2 was frequently decreased in RCC and lung cancer tissues compared with the corresponding levels in normal adjacent tissues. The restoration of SUSD2 expression inhibited the proliferation and clonogenicity of RCC and lung cancer cells, whereas the knockdown of SUSD2 promoted A549 cell growth. Our findings suggested that SUSD2 functions as a tumor suppressor gene (TSG) in RCC and lung cancer.

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Erratum to: Decreased expression of MEG3 contributes to retinoblastoma progression and affects retinoblastoma cell growth by regulating the activity of Wnt/β-catenin pathway

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miR-15a and miR-24-1 as putative prognostic microRNA signatures for pediatric pilocytic astrocytomas and ependymomas

Abstract

In the current setting, we attempted to verify and validate miRNA candidates relevant to pediatric primary brain tumor progression and outcome, in order to provide data regarding the identification of novel prognostic biomarkers. Overall, 26 resected brain tumors were studied from children diagnosed with pilocytic astrocytomas (PAs) (n = 19) and ependymomas (EPs) (n = 7). As controls, deceased children who underwent autopsy and were not present with any brain malignancy were used. The experimental approach included microarrays covering 1211 miRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the expression profiles of miR-15a and miR-24-1. The multiparameter analyses were performed with MATLAB. Matching differentially expressed miRNAs were detected in both PAs and EPs, following distinct comparisons with the control cohort; however, in several cases, they exhibited tissue-specific expression profiles. On correlations between miRNA expression and EP progression or outcome, miR-15a and miR-24-1 were found upregulated in EP relapsed and EP deceased cases when compared to EP clinical remission cases and EP survivors, respectively. Taken together, following several distinct associations between miRNA expression and diverse clinical parameters, the current study repeatedly highlighted miR-15a and miR-24-1 as candidate oncogenic molecules associated with inferior prognosis in children diagnosed with ependymoma.

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Naive Treg-like CCR7 + mononuclear cells indicate unfavorable prognosis in hepatocellular carcinoma

Abstract

Chemokine receptor-like 1 (CCRL1) has the potential in creating a low level of CCL19 and CCL21 to hinder CCR7⁺ cell tracking to tumor tissue. Previously, we found a tumor suppressive role of CCRL1 by impairing CCR7-related chemotaxis of tumor cells in human hepatocellular carcinoma (HCC). Here, we reported a contribution of CCR7⁺ mononuclear cells in the tumor microenvironment to the progression of disease. Immunohistochemistry was used to investigate the distribution and clinical significance of CCR7⁺ cells in a cohort of 240 HCC patients. Furthermore, the phenotype, composition, and functional status of CCR7⁺ cells were determined by flow cytometry, immunofluorescence, and in vitro co-culture assays. We found that CCR7⁺ mononuclear cells were dispersed around tumor tissue and negatively related to tumoral expression of CCRL1 (P < 0.001, r = 0.391). High density of CCR7⁺ mononuclear cells positively correlated with the absence of tumor capsule, vascular invasion, and poor differentiation (P < 0.05). Survival analyses revealed that increased number of CCR7⁺ mononuclear cells was significantly associated with worse survival and increased recurrence. We found that CCR7⁺ mononuclear cells featured a naive Treg-like phenotype (CD45RA⁺CD25⁺FOXP3⁺) and possessed tumor-promoting potential by producing TGF-β1. Moreover, CCR7⁺ cells were also composed of several immunocytes, a third of which were CD8⁺ T cells. CCR7⁺ Treg-like cells facilitate tumor growth and indicate unfavorable prognosis in HCC patients, but fortunately, their tracking to tumor tissue is under the control of CCRL1.

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The cancer-retina antigen recoverin as a potential biomarker for renal tumors

Abstract

The renal cell carcinoma is the ninth most common cancer with an increasing occurrence and mortality. Recoverin is the first retina-specific photoreceptor protein that was shown to undergo aberrant expression, due to its promoter demethylation, as a cancer-retina antigen in a number of malignant tumors. In this work, we demonstrated that recoverin is indeed expressed in 68.4 % of patients with different subtypes of renal cell carcinoma, and this expression has tendency to correlate with tumor size. Interestingly, 91.7 % of patients with the benign renal tumor, oncocytoma, express recoverin as well in their tumor. Epigenetic analysis of the recoverin gene promoter revealed a stable mosaic methylation pattern with the predominance of the methylated state, with the exception of -80 and 56 CpG dinucleotides (CpGs). While the recoverin expression does not correlate withoverall survival of the tumor patients, the methylation of the recoverin gene promoter at -80 position is associated with better overall survival of the patients. This work is the first report pointing towards the association of overall survival of renal cell carcinoma (RCC) patients with promoter methylation of a cancer-retina antigen. Taken together, these data allow to consider recoverin as a potential therapeutic target and/or marker for renal tumors.

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Trophoblastic-like tumor phenotype, a key to oncogenesis

Publication date: Available online 27 January 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Jean Piechowski
The epigenetic plasticity of cancer stem-like cells allows them to reprogram multifaceted properties. Being determined by an oncogene driving force, the reprogrammed properties are suitable for extensive, non-homeostatic clone expansion rather than controlled tissue generation. They belong to physiological phenotypes, under strict control in normal cells but illicitly expressed in malignant cells. Comparing the embryo nidation implemented by trophoblast with tumor progression, it clearly appears that trophoblastic and cancerous cells share strongly similar behavior and logistical properties, likely making the trophoblastic phenotype a core component of the malignant phenotype. By reprogramming it, malignant cells acquire a coordinated set of functions very efficient for survival, protection, expansion and migration. This phenotype seems to have not yet been experimentally studied in depth as to its contribution to oncogenesis. We suggest opening a specific field of research on malignant cells and host tissue receptivity, guided by the relationship between nidation and tumor implantation.



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