Cancer by Sfakianakis Alexandros: 07/28/16

Πέμπτη 28 Ιουλίου 2016

Association of variants in BAFF (rs9514828 and rs1041569) and BAFF-R (rs61756766) genes with the risk of chronic lymphocytic leukemia

Abstract

The B-cell activator factor (BAFF)/BAFF receptor (BAFF-R) axis seems to play an important role in the development and progression of chronic lymphocytic leukemia (CLL). Here, we investigated the association of eight single nucleotide polymorphisms (SNPs) in the BAFF (TNFSF13B) and BAFF-R (TNFRSF13C) genes with risk of sporadic CLL in a group of 439 CLL patients and 477 controls. We also examined the correlation between selected SNPs and CLL clinical parameters as well as BAFF plasma levels and intracellular BAFF expression. Our results point to a possible association between the rs9514828 (CT vs. CC + TT; OR = 0.74; CI 95 % = 0.57; 0.97; p = 0.022) and rs1041569 (AT vs. AA + TT; OR = 0.72; CI 95 % = 0.54; 0.95; p = 0.021) of BAFF gene and rs61756766 (CC vs. CT; OR = 2.03; CI 95 % = 1.03; 3.99; p = 0.03) of BAFF-R gene and CLL risk. Additionally, we observed that homozygotes rs1041569 AA and TT had a slightly higher risk (HR = 1.12) for the need of treatment in comparison to AT heterozygotes. In conclusion, our results indicate that SNPs in BAFF and BAFF-R genes may be considered as potential CLL risk factors.

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Biomarkers of genome instability and cancer epigenetics

Abstract

Tumorigenesis is a multistep process involving genetic and epigenetic alterations that drive somatic evolution from normal human cells to malignant derivatives. Collectively, genetic and epigenetic alterations might be combined into biomarkers for the assessment of risk, the detection of early stage tumors, and accurate tumor characterization before and after treatment. Recent efforts have provided systematic approaches to cancer genomics through the application of massive sequencing of specific tumor types. Here, we review biomarkers of genome instability and epigenetics. Cancer evolvability and adaptation emerge through genetic and epigenetic lesions of a variety of sizes and qualities—from point mutations and small insertions/deletions to large-scale chromosomal rearrangements, alterations in whole chromosome copy number, preferential allelic expression of cancer risk alleles, and mechanisms that increase tumor mutation rates. We also review specific epigenetic mechanisms that facilitate or hinder tumor adaptation, including DNA methylation, histone modification, nucleosome remodeling, transcription factor activity, and small non-coding RNAs. Given the complexity of the carcinogenic process, the challenge ahead will be to interpret disparate signals across hundreds of genes and summarize these signals into a single actionable diagnosis that translates into specific treatments. Another challenge is to refine preventive efforts through the identification of epigenetic processes that mediate increased cancer rates in individuals exposed to sources of toxic environmental stress and pollution, specially through development and early childhood.

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miRNA-regulated cancer stem cells: understanding the property and the role of miRNA in carcinogenesis

Abstract

Over the last few years, microRNAs (miRNA)-controlled cancer stem cells have drawn enormous attention. Cancer stem cells are a small population of tumor cells that possess the stem cell property of self-renewal. Recent data shows that miRNA regulates this small population of stem cells. In the present review, we explained different characteristics of cancer stem cells as well as miRNA regulation of self-renewal and differentiation in cancer stem cells. We also described the migration and tumor formation. Finally, we described the different miRNAs that regulate various types of cancer stem cells, such as prostate cancer stem cells, head and neck cancer stem cells, breast cancer stem cells, colorectal cancer stem cells, lung cancer stem cells, gastric cancer stem cells, pancreatic cancer stem cells, etc. Extensive research is needed in order to employ miRNA-based therapeutics to control cancer stem cell population in various cancers in the future.

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Downregulated expression of DIXDC1 in hepatocellular carcinoma and its correlation with prognosis

Abstract

Dishevelled-Axin domain containing 1 (DIXDC1) is a DIX (Dishevelled-Axin) domain possessing protein that acts as a positive regulator of the Wnt pathway. Although DIXDC1 has been investigated in several cancers, it has not yet been studied in human hepatocellular carcinoma (HCC). The purpose of the current study was to investigate the expression pattern of DIXDC1 and assess the clinical significance of DIXDC1 expression in HCC patients. Data containing three independent investigations from Oncomine database demonstrated that DIXDC1 mRNA was downregulated in HCC compared with matched non-cancerous tissues. Similar results were also obtained in 25 paired HCC tissues and corresponding non-cancerous tissues by qPCR and Western blot analysis. Additionally, another independent set of 140 pairs of HCC specimens was evaluated for DIXDC1 expression by IHC and demonstrated that reduced expression of DIXDC1 in 50.7 % (71/140) of HCC tissues was significantly correlated with tumor size (p = 0.024), tumor differentiation (p < 0.001), tumor thrombi (p = 0.019), TNM stage (p = 0.019), and BCLC stage (p = 0.008). Importantly, Kaplan–Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC patients and found that DIXDC1 protein expression was one of the independent prognostic factors for overall survival of HCC patients.

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Identification of aldolase A as a potential diagnostic biomarker for colorectal cancer based on proteomic analysis using formalin-fixed paraffin-embedded tissue

Abstract

Colorectal cancer (CRC) is one of the most common cancers worldwide, and many patients are already at an advanced stage when they are diagnosed. Therefore, novel biomarkers for early detection of colorectal cancer are required. In this study, we performed a global shotgun proteomic analysis using formalin-fixed and paraffin-embedded (FFPE) CRC tissue. We identified 84 candidate proteins whose expression levels were differentially expressed in cancer and non-cancer regions. A label-free semiquantitative method based on spectral counting and gene ontology (GO) analysis led to a total of 21 candidate proteins that could potentially be detected in blood. Validation studies revealed cyclophilin A, annexin A2, and aldolase A mRNA and protein expression levels were significantly higher in cancer regions than in non-cancer regions. Moreover, an in vitro study showed that secretion of aldolase A into the culture medium was clearly suppressed in CRC cells compared to normal colon epithelium. These findings suggest that decreased aldolase A in blood may be a novel biomarker for the early detection of CRC.

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Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO/EPO-R system and hypoxia-related proteins

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas. There is great interest to know the molecular basis of the tumor biology of ccRCC that might contribute to a better understanding of the aggressive biological behavior of this cancer and to identify early biomarkers of disease. This study describes the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (hypoxia-inducible factor (HIF)-1α, erythropoietin (EPO), vascular endothelial growth factor (VEGF)), their receptors (EPO-R, VEGFR-2), and stearoyl desaturase-1 (SCD-1) in early stages of ccRCC. Tissue samples were obtained at the Urology Unit of the J.R. Vidal Hospital (Corrientes, Argentina), from patients who underwent radical nephrectomy for renal cancer between 2011 and 2014. Four experimental groups according to pathological stage and nuclear grade were organized: T1G1 (n = 6), T2G1 (n = 4), T1G2 (n = 7), and T2G2 (n = 7). The expression of HIF-1α, EPO, EPO-R, VEGF, VEGFR-2, Bcl-x_L, and SCD-1 were evaluated by immunohistochemistry, Western blotting, and/or RT-PCR. Apoptosis was assessed by the TUNEL in situ assay, and tumor proliferation was determined by Ki-67 immunohistochemistry. Data revealed that HIF-1α, EPO, EPO-R, VEGF, and VEGF-R2 were overexpressed in most samples. The T1G1 group showed the highest EPO levels, approximately 200 % compared with distal renal tissue. Bcl-x_L overexpression was concomitant with the enhancement of proliferative indexes. SCD-1 expression increased with the tumor size and nuclear grade. Moreover, the direct correlations observed between SCD-1/HIF-1α and SCD-1/Ki-67 increments suggest a link among these molecules, which would determine tumor progression in early stages of ccRCC. Our results demonstrate the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (HIF-1α, EPO, VEGF), their receptors (EPO-R, VEGFR-2), and SCD-1 in early stages of ccRCC.

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Birinapant and radiation in HNSCC

Comparison of tumors from the Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus Inhibitor of Apoptosis repeat containing BIRC2 (cIAP1), affecting ~30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR and Western blot. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation. Birinapant, a novel SMAC mimetic, sensitized multiple HNSCC lines to cell death by agonists TNFαalpha or TRAIL, and inhibited cIAP1>XIAP>IAP2. Combination of birinapant and TNFα induced sub-G0 DNA fragmentation in sensitive lines, and birinapant alone also induced significant G2/M cell cycle arrest and cell death in UM-SCC-46 cells. Gene transfer and expression of FADD sensitized resistant UM-SCC-38 cells lacking FADD amplification to birinapant and TNFalpha, supporting a role for FADD in sensitization to IAP inhibitor and death ligands. HNSCC varied in mechanisms of cell death, as indicated by reversal by inhibitors or protein markers of caspase-dependent apoptosis and/or RIPK1/MLKL-mediated necroptosis. In vivo, birinapant inhibited tumor growth and enhanced radiation induced TNFalpha, tumor responses, and host survival in UM-SCC-46 and -11B xenograft models displaying amplification and overexpression of FADD+/-BIRC2. These findings suggest that combination of SMAC mimetics such as birinapant plus radiation may be particularly active in HNSCC, which harbor frequent FADD/BIRC2 genomic alterations.

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Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline

Abstract

Purpose

To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data.

Methods

Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated.

Results

A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79].

Conclusion

A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.

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Protein expression of ATP-binding cassette transporters ABCC10 and ABCC11 associates with survival of colorectal cancer patients

Abstract

Purpose

This study investigated the prognostic importance of protein expression of ATP-binding cassette (ABC) transporters ABCC10 and ABCC11 in colorectal cancer.

Methods

Protein content of ABCC10 and ABCC11 was assessed in tumor tissue blocks of 140 colorectal cancer patients and associated with survival of patients with regard to 5-fluorouracil-based therapy.

Results

Low ABCC10 protein content in tumors increased hazard ratio of patient's death more than three times in comparison with high ABCC10-expressing tumors (P = 0.004). In contrast, the low ABCC11 content increased the hazard ratio of cancer recurrence in patients almost four times (P = 0.016). Analysis of patients treated with regimens based on 5-fluorouracil revealed that patients with low ABCC11 content in their tumors had shorter disease-free interval than those with higher content (P = 0.024).

Conclusions

The present study shows for the first time that the protein expression of ABCC10 significantly associates with overall survival and the expression of ABCC11 with disease-free interval of colorectal cancer patients and provides strong impulse for further validation of their prognostic value in colorectal cancer.

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Association of variants in BAFF (rs9514828 and rs1041569) and BAFF-R (rs61756766) genes with the risk of chronic lymphocytic leukemia

Abstract

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Biomarkers of genome instability and cancer epigenetics

Abstract

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Identification of MGMT promoter methylation sites correlating with gene expression and IDH1 mutation in gliomas

Abstract

O⁶-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation was reported to be an independent prognostic and predictive factor in glioma patients who received temozolomide treatment. However, the predictive value of MGMT methylation was recently questioned by several large clinical studies. The purpose of this study is to identify MGMT gene promoter CpG sites or region whose methylation were closely correlated with its gene expression to elucidate this contradictory clinical observations. The methylation status for all CpG dinucleotides in MGMT promoter and first exon region were determined in 42 Chinese glioma patients, which were then correlated with MGMT gene expression, IDH1 mutation, and tumor grade. In whole 87 CpG dinucleotides analyzed, three distinct CpG regions covering 28 CpG dinucleotides were significantly correlated with MGMT gene expression; 10 CpG dinucleotides were significantly correlated with glioma classification (p < 0.05). Isocitrate dehydrogenase 1 (IDH1) mutation and MGMT gene hypermethylation significantly co-existed, but not for MGMT gene expression. The validation cohort of gliomas treated with standard of care and comparison of the CpGs we identified with the current CpGs used in clinical setting will be very important for gliomas individual medicine in the future.

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miRNA-regulated cancer stem cells: understanding the property and the role of miRNA in carcinogenesis

Abstract

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Downregulated expression of DIXDC1 in hepatocellular carcinoma and its correlation with prognosis

Abstract

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Identification of aldolase A as a potential diagnostic biomarker for colorectal cancer based on proteomic analysis using formalin-fixed paraffin-embedded tissue

Abstract

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Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO/EPO-R system and hypoxia-related proteins

Abstract

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PD-1 axis inhibitors in EGFR and ALK Driven Lung Cancer

Programmed death axis 1 (PD-1) inhibitors have ushered in a new error of cancer immuno-therapeutics for advanced smoking associated non-small cell lung cancer. Their role in treating EGFR mutant and ALK rearranged lung cancer has yet to be determined.

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Individualized pazopanib dosing

Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median PFS and tumor shrinkage appears in patients with higher plasma trough levels (C_min). Therefore, patients with low C_min might benefit from pharmacokinetically-guided individualized dosing. Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib C_min was measured weekly by LC-MS/MS. At week 3, 5 and 7 the pazopanib dose was increased if the measured C_min was <20 mg/L and toxicity was < grade 3. Results: In total, 17 patients had at least one C_min <20 mg/L at week 3, 5 and 7. Of these, 10 were successfully treated with a pharmacokinetically-guided dose escalation, leading to daily dosages ranging from 1000 to 1800 mg daily. C_min in these patients increased significantly from 13.2 (38.0%) mg/L (mean (CV%)) to 22.9 mg/L (44.9%). Thirteen patients had all C_min levels {greater than or equal to}20 mg/L. Of these, nine patients with a high C_min of 51.3 mg/L (45.1%) experienced {greater than or equal to} grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients C_min remained above the threshold at 28.2 mg/L (25.3%). Conclusions: A pharmacokinetically-guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes such as progression free survival.

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PD-1/PD-L1 in GIST

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumor (GIST), but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GIST. Experimental Design: We analyzed tumor and matched blood samples from 85 patients with GIST and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558/+ mice that develop GIST. Results: The inhibitory receptors PD-1, lymphocyte activation gene 3 (LAG-3), and T cell immunoglobulin mucin-3 (TIM-3) were upregulated on tumor-infiltrating T cells compared to T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFN--induced upregulation of PD-L1 via STAT1 inhibition. In KitV558/+ mice imatinib downregulated IFN--related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone, but enhanced the antitumor effects of imatinib by increasing T cell effector function in the presence of KIT and IDO inhibition. Conclusions: PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GIST. Collectively, our results provide the rationale to combine these agents in human GIST.

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The role of local ablative therapy in oligometastatic non-small-cell lung cancer: hype or hope

Future Oncology Ahead of Print.

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Addressing psychosocial issues in cancer survivorship: past, present and future

Future Oncology Ahead of Print.

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Selumetinib in the treatment of non-small-cell lung cancer

Future Oncology Ahead of Print.

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EYA4 gene functions as a prognostic marker and inhibits the growth of intrahepatic cholangiocarcinoma

The molecular prognostic markers and carcinogenesis of intrahepatic cholangiocarcinoma (ICC) have not been well documented. The purpose of this study was to investigate the prognostic value of the eyes absent ...

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The role of local ablative therapy in oligometastatic non-small-cell lung cancer: hype or hope

Future Oncology Ahead of Print.

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Addressing psychosocial issues in cancer survivorship: past, present and future

Future Oncology Ahead of Print.

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Selumetinib in the treatment of non-small-cell lung cancer

Future Oncology Ahead of Print.

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ATRX loss in glioneuronal tumors with neuropil-like islands indicates similarity to diffuse astrocytic tumors

Abstract

Glioneuronal tumor with neuropil-like islands (GTNI) is a rare, recently described neoplasm, whose pathogenesis has not been studied extensively. The role of ATRX mutations, a class-defining alteration in diffuse astrocytic neoplasms, has not been assessed in GTNIs previously. We therefore aimed to assess the status of ATRX, along with IDH1, 1p/19q and p53, in cases of GTNI in order to evaluate the molecular profile of these tumors. All cases of GTNI diagnosed at our Institute were retrieved and clinicopathological features were reviewed. Immunohistochemistry for ATRX, IDH1 and p53 was performed. We identified four cases of GTNI, majority of which occurred in young adults. Loss of ATRX immunoexpression, a surrogate marker for ATRX mutation, was seen in all four cases. All cases were immunopositive for p53, while IDH1 positivity was seen in all three cases assessed. 1p/19q codeletion was absent in the three cases analyzed. These results indicate that the molecular pathogenesis of GTNIs similar to that of diffuse astrocytic tumors. Further, the loss of ATRX expression is seen in both the glial as well as neuronal components, indicating that both arise from the same tumor stem/progenitor cell and that the latter may be a metaplastic change. Thus, loss of ATRX immunoexpression, shown for the first time in these tumors, along with immunopositivity for p53 and IDH1, indicates that these tumors are molecular astrocytomas, and their clinical behaviour is likely to recapitulate that of ATRX-mutant and IDH-mutant diffuse astrocytomas of the same grade.

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The effect of lengthening contractions on neuromuscular junction structure in adult and old mice

Abstract

Skeletal muscles of old mice demonstrate a profound inability to regenerate fully following damage. Such a failure could be catastrophic to older individuals where muscle loss is already evident. Degeneration and regeneration of muscle fibres following contraction-induced injury in adult and old mice are well characterised, but little is known about the accompanying changes in motor neurons and neuromuscular junctions (NMJs) following this form of injury although defective re-innervation of muscle following contraction-induced damage has been proposed to play a role in sarcopenia. This study visualised and quantified structural changes to motor neurons and NMJs in Extensor digitorum longus (EDL) muscles of adult and old Thy1-YFP transgenic mice during regeneration following contraction-induced muscle damage. Data demonstrated that the damaging contraction protocol resulted in substantial initial disruption to NMJs in muscles of adult mice, which was reversed entirely within 28 days following damage. In contrast, in quiescent muscles of old mice, ∼15 % of muscle fibres were denervated and ∼80 % of NMJs showed disruption. This proportion of denervated and partially denervated fibres remained unchanged following recovery from contraction-induced damage in muscles of old mice although ∼25 % of muscle fibres were completely lost by 28 days post-contractions. Thus, in old mice, the failure to restore full muscle force generation that occurs following damage does not appear to be due to any further deficit in the percentage of disrupted NMJs, but appears to be due, at least in part, to the complete loss of muscle fibres following damage.

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Reliability and Responsiveness of NutriQoL ® Questionnaire

Abstract

Introduction

NutriQoL^® (Nestlé Health Science, Vevay, Switzerland) is a questionnaire developed to assess the health-related quality-of-life (HRQoL) of patients with home enteral nutrition (HEN) irrespective of their underlying condition and route of administration. The aim of this work is assessing the questionnaire's reliability and responsiveness to change.

Methods

Two cohorts of patients with HEN and their primary caregivers were enrolled to assess reliability and responsiveness, respectively. All participants had to be 18 years of age or older, without mental deterioration (≤3 or 4 errors in the Pfeiffer's test) and with sufficient functional status (>40 points on Karnovsky's performance status scale). When the patients' ability to respond to the questionnaire was impaired due to underlying disease, their caregivers answered on their behalf. NutriQoL was administered in two and three visits to reliability and responsiveness cohorts, respectively. Test–retest reliability and internal consistency were assessed by the intra-class correlation coefficient (ICC) and the Cronbach's α, respectively. Responsiveness was evaluated by standardized effect size and standardized response mean between basal visit and third visit. Finally, the minimal clinically important difference (MCID) was estimated.

Results

A total of 54 and 86 participants were recruited to the reliability and responsiveness cohort, respectively. Thirty-five caregivers were selected to assess the inter-observer reliability. ICC values confirmed the good reproducibility level (ICC >0.75) of the questionnaire in both "physical functioning and activities of daily living" and "social life" domains and total score. The assessment of internal consistency in both domains of the questionnaire showed good internal consistency in visit 2. ICC showed the excellent agreement level between caregiver and patient in the global NutriQoL score. Finally, patients classified as having a minimal change in their health reported a mean (standard deviation) MCID in NutriQoL score of 0.63 (11.51).

Conclusion

NutriQoL is a reliable and unique instrument to measure the HRQoL in HEN patients. NutriQoL detects changes in the health status of the patient. Nevertheless, further research is needed to determine the full extent of the questionnaire responsiveness.

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Associations of objectively measured moderate-to-vigorous physical activity and sedentary behavior with quality of life and psychological well-being in prostate cancer survivors

Abstract

Purpose

Although evidence is building on the positive effects of physical activity for prostate cancer survivors, less is known about the possible independent effects of sedentary behavior on quality of life and psychological well-being in this population. We determined the extent to which objectively measured moderate-to-vigorous physical activity (MVPA) and sedentary behavior were independently associated with quality of life, anxiety, and depressive symptoms in prostate cancer survivors.

Methods

An exploratory cross-sectional analysis was undertaken on baseline data from a multicenter, cluster randomized controlled trial on the efficacy of a clinician referral and 12-week exercise program for men who had completed active treatment for prostate cancer. Multiple regression analyses were performed using data from 98 prostate cancer survivors who wore hip-mounted accelerometers (time spent sedentary defined as <100 counts per minute [CPM]; MVPA defined as >1,951 CPM) and completed self-report instruments on their quality of life, anxiety, and depressive symptoms. Results were compared with minimal clinically important differences for the quality of life scales.

Results

Independent of sedentary behavior, increases in MVPA of between 15 and 33 min/day were associated with clinically important (but not statistically significant) improvements in three quality of life scales (insomnia, diarrhea, and financial difficulties). Independent of MVPA, decreases in sedentary behavior of 119 and 107 min/day were associated with clinically important (but not statistically significant) improvements in physical functioning and role functioning, respectively.

Conclusion

Within our exploratory study, modest increases in MVPA and more substantive decreases in sedentary behavior were independently associated with clinically important improvements in several quality of life scales. Further research, including prospective studies, is required to understand sedentary behavior across larger and more representative samples (in terms of their physical, psychological, and social functioning and their engagement in physical activity) of prostate cancer survivors.

Trial registration

Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000609055

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Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline

Abstract

Purpose

To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data.

Methods

Results

Conclusion

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Protein expression of ATP-binding cassette transporters ABCC10 and ABCC11 associates with survival of colorectal cancer patients

Abstract

Purpose

This study investigated the prognostic importance of protein expression of ATP-binding cassette (ABC) transporters ABCC10 and ABCC11 in colorectal cancer.

Methods

Protein content of ABCC10 and ABCC11 was assessed in tumor tissue blocks of 140 colorectal cancer patients and associated with survival of patients with regard to 5-fluorouracil-based therapy.

Results

Conclusions

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Glossaire de radiothérapie

Publication date: Available online 28 July 2016
Source:Cancer/Radiothérapie

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Urinary circulating DNA detection for dynamic tracking of EGFR mutations for NSCLC patients treated with EGFR-TKIs

Abstract

Purpose

Changes in EGFR profiles of non small cell lung cancer (NSCLC) patients correlates to clinical outcome. Extracting quality tumor tissue remains a challenge for molecular profiling. Our study aims to ascertain the clinical relevance of urinary cell free DNA as an alternative tumor material source.

Methods

150 patients with activating EGFR mutation and received EGFR-TKIs were recruited to participate in the serial monitoring study. Matched primary tumor samples were taken together with blood and urine specimens before the initiation of TKIs. The EGFR mutation testing was performed and quantified using ddPCR. For serial time point measurements, urine and blood samples were extracted at 1-month intervals for duration of 9 months.

Results

Urinary ctDNA yielded a close agreement of 88 % on EGFR mutation status when compared to primary tissue at baseline. Almost all samples detected via urine specimens were uncovered in plasma samples. Analysis of urinary cell free DNA at different time points showed a strong correlation to treatment efficacy. Interestingly, a secondary EGFR mutation T790M was detected for 53 % of the patients during monitoring. The results were corroborated with the plasma ctDNA analysis. The T790M+ group had a reduced median survival when compared to the wildtype group.

Conclusion

Urinary cell free DNA may be a potential alternative to conventional primary tissue based EGFR mutation testing. Our findings showed that the assay sensitivity was comparable to results from blood plasma. Urinary samples being noninvasive and readily available have clinical utility for monitoring of EGFR TKI treatment.

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Selective internal radiation therapy with 90Y glass microspheres: biases and uncertainties in absorbed dose calculations between clinical dosimetry models

Publication date: Available online 27 July 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Justin K. Mikell, Armeen Mahvash, Wendy Siman, Veera Baladandayuthapani, Firas Mourtada, S. Cheenu Kappadath
PurposeQuantify differences that exist between dosimetry models used for ⁹⁰Y selective internal radiation therapy (SIRT).Methods and MaterialsRetrospectively, 37 tumors were delineated on 19 post-therapy quantitative ⁹⁰Y SPECT/CT. Using matched volumes of interest (VOI), absorbed doses (AD) were reported using three dosimetry models: glass microsphere package insert standard model (SM), partition model (PM), and Monte Carlo (MC). Univariate linear regressions were performed to predict mean MC from SM and PM. Analysis was performed for two subsets: cases with a single tumor delineated (best case for PM); and cases with multiple tumors delineated (typical clinical scenario). Variability in PM from the ad hoc placement of a single spherical VOI to estimate the entire normal liver activity concentration for tumor (T) to non-tumoral liver (NL) ratios (TNR) was investigated. We interpreted the slope of the resulting regression as bias and the 95% prediction interval (95%PI) as uncertainty. MCNLsingle represents MC absorbed doses to the NL for the single tumor patient subset; other combinations of calculations follow a similar naming convention.ResultsSM was unable to predict MCTsingle or MCTmultiple (p>0.12, 95%PI>±177 Gy). However, SMsingle was able to predict (p<0.012) MCNLsingle, albeit with large uncertainties; SMsingle and SMmultiple yielded biases of 0.62 and 0.71, and 95%PI of ±40 and ±32 Gy, respectively. PMTsingle and PMTmultiple predicted (p<2E-6) MCTsingle and MCTmultiple with biases of 0.52 and 0.54, and 95%PI of ±38 and ±111 Gy, respectively. TNR variability in PMTsingle increased the 95%PI for predicting MCTsingle (bias=0.46 and 95%PI=±103 Gy). TNR variability in PMTmultiple modified the bias when predicting MCTmultiple (bias=0.32 and 95%PI=±110 Gy).ConclusionsSM is unable to predict mean MC tumor absorbed dose. PM is statistically correlated with mean MC, but the resulting uncertainties in predicted MC are large. Large differences observed between dosimetry models for ⁹⁰Y SIRT warrant caution when interpreting published SIRT absorbed doses. To reduce uncertainty, we suggest the entire NL VOI be used for TNR estimates when using PM.

Teaser

Relative to external beam, currently used standard (SM) and partition (PM) dosimetry models for ⁹⁰Y SIRT are simplistic. We show that large differences exist in calculated mean absorbed doses when voxel-level Monte Carlo (MC) calculations are compared to SM and PM absorbed doses. SM is unable to predict individual mean MC tumor absorbed dose. PM is statistically correlated to mean MC absorbed dose, but with large uncertainties in predicted values.

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Urinary circulating DNA detection for dynamic tracking of EGFR mutations for NSCLC patients treated with EGFR-TKIs

Abstract

Purpose

Methods

Results

Conclusion

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Multicenter phase II study of combination therapy with cetuximab and S-1 in patients with KRAS exon 2 wild-type unresectable colorectal cancer previously treated with irinotecan, oxaliplatin, and fluoropyrimidines (KSCC 0901 study)

Abstract

Purpose

Anti-epidermal growth factor receptor antibody therapy alone or in combination with irinotecan is recognized as a standard third-line treatment for KRAS wild-type unresectable metastatic colorectal cancer. However, in some cases, it is difficult to administer irinotecan after third-line treatment. Therefore, we examined the efficacy and safety of the combination of cetuximab and S-1 in patients with KRAS wild-type unresectable metastatic colorectal cancer who were previously treated with irinotecan, oxaliplatin, and fluoropyrimidines.

Methods

The study was designed as a phase II, non-randomized, open-label, multicenter trial. Cetuximab was initially administered at 400 mg/m², followed by weekly infusion at 250 mg/m². S-1 was administered at a fixed dose of 80 mg/m² orally twice daily for 28 days followed by a 14-day break, resulting in a 6-week treatment course. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the overall response rate (ORR), overall survival (OS), disease control rate (DCR), time to treatment failure, dose intensity, safety, and BRAF mutation status.

Results

Thirty-seven patients were eligible. The median PFS was 5.5 months, the median OS was 13.5 months, the ORR was 29.7 %, and the DCR was 73.0 %. The relative dose intensity was 86.8 % for cetuximab and 88.1 % for S-1. Grade 3–4 adverse events that occurred in >10 % of the patient population included rash, dry skin, diarrhea, paronychia, anorexia, fatigue, mucositis, and neutropenia.

Conclusions

Combination therapy with cetuximab and S-1 was effective and well tolerated in patients with irinotecan-, oxaliplatin-, and fluoropyrimidine-refractory metastatic colorectal cancer.

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EYA4 gene functions as a prognostic marker and inhibits the growth of intrahepatic cholangiocarcinoma

Abstract

Background

The molecular prognostic markers and carcinogenesis of intrahepatic cholangiocarcinoma (ICC) have not been well documented. The purpose of this study was to investigate the prognostic value of the eyes absent homolog 4 (EYA4) gene in ICC and its biological effects on ICC growth in vitro and in vivo.

Methods

One hundred twelve patients with ICC who underwent hepatectomy were enrolled in the study. EYA4 mRNA and EYA4 protein levels in ICC and adjacent non-tumoral tissues were evaluated using real-time quantitative polymerase chain reaction and immunohistochemical staining, respectively. EYA4 protein levels in ICC cells were determined using western blot analysis. The associations between EYA4 expression and clinicopathologic features of ICC were analyzed. To identify independent prognostic factors, univariate and multivariate analyses were performed. The biological effects of EYA4 on ICC cells were evaluated by establishing stable EYA4-overexpressing transfectants in vitro, and EYA4's effects on tumor growth were evaluated by intra-tumoral injection of EYA4-expressing plasmids in a NOD/SCID murine model of xenograft tumors.

Results

ICC tissues had significantly lower EYA4 mRNA and protein levels compared with adjacent non-tumoral tissues (both P < 0.001). Univariate and multivariate analyses showed that EYA4 protein level, tumor number, adjacent organ invasion, lymph node metastasis, and tumor differentiation were independent prognostic factors for disease-free survival and overall survival (all P < 0.05). In vitro, EYA4 overexpression inhibited tumor cell growth, foci formation, and cell invasiveness. In vivo, intra-tumoral injection of EYA4-expressing plasmids significantly inhibited ICC growth in the murine xenograft model compared with the control group (P < 0.05).

Conclusion

EYA4 gene functioned as a molecular prognostic marker in ICC, and its overexpression inhibited tumor growth in vitro and in vivo.

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Pay attention to EBSLN in anatomical classification of the superior pole in thyroid surgery

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In response to: Pay attention to EBSLN in anatomical classification of the superior pole in thyroid surgery

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Gliomatosis cerebri: A consensus summary report from the First International Gliomatosis cerebri Group Meeting, March 26–27, 2015, Paris, France

Abstract

Gliomatosis cerebri (GC) is a universally fatal extensive and diffuse infiltration of brain parenchyma by a glial tumor. Many aspects of this phenomenon remain unknown. The First International Gliomatosis cerebri Group Meeting had the following goals: refine the clinical and radiologic diagnostic criteria for GC, suggest appropriate diagnostic procedures, standardize tissue manipulation for histologic and molecular characterization, and prioritize relevant preclinical projects. Also, general treatment recommendations were outlined for the pediatric population. Importantly, this meeting was the starting point for meaningful collaborative international research projects. This review is a consensus summary of discussions shared and conclusions derived from this meeting.

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Retraction.

Retraction.

Anticancer Res. 2015 Jul;35(7):4372

Authors:

PMID: 26124392 [PubMed]

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[Detection and evaluation of malnutrition in oncology: What tools, what type of cancer and for what purposes?]

[Detection and evaluation of malnutrition in oncology: What tools, what type of cancer and for what purposes?]

Bull Cancer. 2016 Jul 22;

Authors: Khan S, Alibay TA, Merad M, DiPalma M, Raynard B, Antoun S

Abstract
Malnutrition is frequently observed in oncology. The consequences on patient survival, chemotherapy toxicities and quality of life need to be identified and treated appropriately. A set of tools are available that enable clinicians to diagnose and detect malnutrition. Each tool must consider three items: the patient's current nutritional status, reduced food intake and the characteristics of the underlying disease. The parameters and thresholds used to detect malnutrition differ according to the objective pursued. It can be economic, increasing the reimbursement of hospital stays, it can help define prognostic risk groups or its purpose can be to initiate nutritional treatment. Recent data support the assessment of parameters such as inflammatory markers, decreased muscle mass (i.e. sarcopenia) whose diagnosis is associated with a worse outcome and the quantification of food intake with simplified methods. The benefit for the patient of detecting malnutrition will be the initiation of a nutritional treatment when its efficacy has been demonstrated. A case in point is the nutritional support provided to malnourished patients before surgery with benefits in terms of mortality and morbidity and in certain head and neck cancer situations where nutritional support is systematically implemented. It is probably relevant to detect and initiate treatment early in order to promote muscle anabolism.

PMID: 27456260 [PubMed - as supplied by publisher]

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[Guidelines for stage I to III melanoma].

[Guidelines for stage I to III melanoma].

Bull Cancer. 2016 Jul 22;

Authors: Guillot B, Dalac S, Denis M, Dupuy A, Emile JF, De La Fouchardiere A, Hindie E, Jouary T, Lassau N, Mirabel X, Piperno Neumann S, De Raucourt S, Vanwijck R

PMID: 27456259 [PubMed - as supplied by publisher]

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[Is FDG TEP CT practice changing in the management of sarcomas in adults?]

[Is FDG TEP CT practice changing in the management of sarcomas in adults?]

Bull Cancer. 2016 Jul 21;

Authors: Kogay M, Thariat J, Benisvy D, Dufour M, Gastaud L, Saada E, Iannessi A, Thyss A

Abstract
BACKGROUND: FDG PET (PET)±computed tomography (CT) has increasingly been used in some areas of oncology imaging. It is sometimes performed outside recommendations, at diagnosis or monitoring of sarcomas. We assessed the value of PET-CT in routine practice in sarcomas.
MATERIAL AND METHODS: All consecutive sarcoma adult patient charts presented at the multidisciplinary sarcoma meeting in a tertiary care center over a period of 10months were examined in order to analyze the performances of PET-CT when available.
RESULTS: Of 232 patients, 50 (21 %) underwent a PET-CT. Sensitivity and specificity of PET-CT were 94.7 %, 57.1 %, respectively. SUV values were highly variable, including for a given histology or grade. PET-CT resulted in practice changing in 14 % of cases. When extrapulmonary metastases are suspected and for some subtypes of sarcomas, PET-CT could provide additional information because in view of its good sensitivity.
CONCLUSION: Given the most frequent pulmonary tropism, first hand chest CT may be sufficient at first diagnostic work-up for the detection of pulmonary metastases. However, the relatively poor specificity suggests that further analyses should be performed to identify clinical situations where PET-CT may be of added value compared to current standards.

PMID: 27452925 [PubMed - as supplied by publisher]

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Heterogeneity of MYCN Amplification in Neuroblastoma at Diagnosis, Treatment, Relapse and Metastasis

ABSTRACT

Amplification of the MYCN gene in neuroblastoma is associated with a poor prognosis and is considered to remain unchanged in post-treatment specimens and metastases. While heterogeneity of MYCN copy number in tumour cells has been reported, serial samples have only been studied in a limited way, and the biologic relevance of this finding is not well understood. We used in situ hybridization on paraffin sections of 102 specimens from 30 patients with MYCN-amplified neuroblastoma to determine MYCN copy number in the primary tumour, pre- and post-treatment, and in metastatic samples. Nineteen cases (63%) showed diffuse MYCN amplification in all samples tested. Nine cases (30%) showed a reduction in MYCN copy number: five cases with diffuse amplification subsequently showed focal amplification, one case with diffuse MYCN amplification showed MYCN gain after treatment, and three focally amplified cases were non-amplified in later specimens. In two cases (7%), focal amplification became diffuse in subsequent samples. Histology was not predictive of the temporal or spatial pattern of MYCN amplification for a particular tumour. If extent of amplification (focal vs. diffuse) is not considered, 26/30 (87%) of cases were consistently MYCN-amplified. However, our data suggest that MYCN status can be heterogeneous between tumour sites, during tumour progression or following treatment, challenging the notion that MYCN copy number does not change for a particular neuroblastoma. Assessing the biologic significance of MYCN heterogeneity will require larger studies of clinically annotated tumour samples, and will depend on interpreting heterogeneity in MYCN status in combination with other genetic changes. This article is protected by copyright. All rights reserved.

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hTERT promoter methylation in meningiomas and central nervous hemangiopericytomas

Abstract

In meningiomas, prognostic impact of mutations in the human telomerase reverse transcriptase (hTERT) promoter region was recently shown, while studies of promoter methylation and analyses of hemangiopericytomas are lacking. hTERT promoter methylation was analyzed in 78 meningioma and 38 meningeal hemangiopericytoma samples by methylation-specific polymerase chain reaction (MS-PCR) and compared with histopathological and clinical variables and with immunohistochemical hTERT expression. Promoter methylation was found in 62 samples (53 %) and tended to be higher in meningiomas (N = 19/41, 46 %) than in hemangiopericytomas (N = 8/33, 24 %, p = .057). In meningiomas, methylation was 16, 60 and 77 % in grade I, II and III tumors (p < .001) and higher in recurrent (N = 33/37, 89 %) than in primary diagnosed (N = 19/41, 46 %) tumors (OR 5.14, 95 % CI 1.34–19.71, p = .017). Univariate analyses showed shorter mean progression free and overall survival in methylated than in unmethylated individuals (26 vs. 100 months; p = .045 and 110 vs. 113 months; p = .025, respectively). Moreover, hTERT expression was found in 70 % (N = 53) and was more frequent in methylated than in unmethylated samples (78 vs. 52 %, OR 3.36, 95 % CI 1.20–9.40, p = .021). In hemangiopericytomas, methylation was similar in grade II (24 %) and III (25 %, p > .05) and in primary (24 %) and recurrent tumors (40 %, p > .05). hTERT expression was similar as compared to meningiomas (74 %, N = 28, p > .05) but was independent of promoter methylation (OR 4.26, 95 % CI 0.47–39.0, p = .199). In meningeal tumors, hTERT promoter methylation is more common than mutations and in meningiomas but not in hemangiopericytomas positively correlated with WHO grade and hTERT expression.

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M30/M65 ratio predicts the outcome of paclitaxel chemotherapy for NSCLC

Abstract

Purpose

Paclitaxel is an effective treatment for some of the non-small-cell lung cancer (NSCLC) patients. However, prediction of the outcome of paclitaxel treatment at the early stage of the chemotherapy is difficult. M30 and M65 are circulating fragments of cytokeratin 18 released during apoptosis or necrosis, respectively, and have been used as markers to evaluate chemotherapy in some cancers. Here, we aimed to examine M30 and M65 values for predicting the therapeutic outcome of paclitaxel treatment of NSCLC.

Methods

The serum levels of M30 and M65 before and after paclitaxel treatment in advance-stage NSCLC patients were analyzed, and compared to those in healthy controls. The importance of the M30 and M65 levels to the outcome of chemotherapy was analyzed.

Result

We found that the serum M30 and M65 levels were higher in patients with NSCLC (n = 44) than in control healthy subjects (n = 56) (p < 0.001). Two days after paclitaxel treatment, the serum levels of both M30 and M65 significantly increased in NSCLC patients (p < 0.001). Neither marker alone significantly correlated with overall patient survival, but the ratio of M30 vs M65 appeared to be an important prognostic factor for the overall survival of the patients (p < 0.01).

Conclusion

Our results suggest that the serum M30/M65 ratio may be a prognostic factor for the outcome of paclitaxel treatment in NSCLC.

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hTERT promoter methylation in meningiomas and central nervous hemangiopericytomas

Abstract

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Calcium intake and colorectal cancer risk: Results from the Nurses' Health Study and Health Professionals Follow-up Study

Abstract

The relationship between calcium intake and colorectal cancer (CRC) risk remains inconclusive. We conducted this study to evaluate whether the association between calcium intake and CRC risk differs by anatomic subsite and determine the dose-response relationship for this association, as well as assess when in carcinogenesis calcium may play a role. We assessed calcium intake every 4 years and followed 88,509 women (1980-2012) in the Nurses' Health Study and 47,740 men (1986-2012) in the Health Professionals Follow-Up Study. We documented 3,078 incident CRC cases. Total calcium intake (≥1400 vs. <600 mg/d) was associated with a statistically significant lower risk of colon cancer (multivariable relative risk: 0.78, 95%CI: 0.65-0.95). Similar results were observed by different sources of calcium (from all foods or dairy products only). The inverse association was linear and suggestively stronger for distal colon cancer (0.65, 0.43-0.99) than for proximal colon cancer (0.94, 0.72-1.22, P-_{common effects}=0.14). Additionally, when comparing different latencies, the overall pattern suggested that the inverse association appeared to be stronger with increasing latency and was strongest for intakes 12-16 years before diagnosis. Comparing total calcium intakes of ≥1400 vs. <600 mg/d for intake 12–16 y before diagnosis, the pooled RR (95% CIs) of CRC was 0.76 (0.64-0.91). Higher calcium intake was associated with a lower risk of developing colon cancer, especially for distal colon cancer. Overall inverse association was linear and did not differ by intake source. Additionally, calcium intake approximately 10 years before diagnosis appeared to be associated with a lower risk of CRC. This article is protected by copyright. All rights reserved.

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Informing aetiologic research priorities for squamous cell oesophageal cancer in Africa: A review of setting-specific exposures to known and putative risk factors

Abstract

Oesophageal squamous cell carcinoma (ESCC) is one of the most common cancers in most Eastern and Southern African countries, but its aetiology has been understudied to date. To inform its research agenda, we undertook a review to identify, of the ESCC risk factors that have been established or strongly suggested worldwide, those with a high prevalence or high exposure levels in any ESCC-affected African setting and the sources thereof. We found that for almost all ESCC risk factors known to date, including tobacco, alcohol, hot beverage consumption, nitrosamines and both inhaled and ingested PAHs, there is evidence of population groups with raised exposures, the sources of which vary greatly between cultures across the ESCC corridor. Research encompassing these risk factors is warranted and is likely to identify primary prevention strategies. This article is protected by copyright. All rights reserved.

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The need for coordination of research activities in pediatric lung diseases

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