http://ift.tt/2gig6Ya
Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 13 Οκτωβρίου 2017
Breast carcinomas with low amplified/equivocal HER2 by Ish: potential supporting role of multiplex ligation-dependent probe amplification
This is a retrospective cross sectional study aimed to verify whether Multiplex Ligation-dependent Probe Amplification (MLPA), a quantitative molecular assay, may represent a valuable reflex test in breast can...
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Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib
Abstract
In this study, we determined the gene expression profiles of bone marrow-derived cell fractions, obtained from normal subjects and Chronic Myeloid Leukemia (CML) patients, that were highly enriched for hematopoietic stem (HSCs) and progenitor (HPCs) cells. Our results indicate that the profiles of CML HSCs and HPCs were closer to that of normal progenitors, whereas normal HSCs showed the most different expression profile of all. We found that the expression profiles of HSCs and HPCs from CML marrow were closer to each other than those of HSCs and HPCs from normal marrow. The major biologic processes dysregulated in CML cells included DNA repair, cell cycle, chromosome condensation, cell adhesion, and the immune response. We also determined the genomic changes in both normal and CML progenitor cells under culture conditions, and found that several genes involved in cell cycle, steroid biosynthesis, and chromosome segregation were upregulated, whereas genes involved in transcription regulation and apoptosis were downregulated. Interestingly, these changes were the same, regardless of the addition of Imatinib (IM) to the culture. Finally, we identified three genes—PIEZO2, RXFP1, and MAMDC2- that are preferentially expressed by CML primitive cells and that encode for cell membrane proteins; thus, they could be used as biomarkers for CML stem cells.
Gene expression profiles of hematopoietic stem and progenitor cells from CML patients have been obtained. The in vitro effect of Imatinib on such gene expression profiles was assessed. Potential leukemic biomarker genes were identified.
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Phosphorylated ERK is a potential prognostic biomarker for Sorafenib response in hepatocellular carcinoma
Abstract
Sorafenib, the only approved drug for hepatocellular carcinoma, acts as a remarkable inhibitor of Raf serine-threonine kinases. However, Sorafenib is expensive, and clinical experience shows that it is not an effective treatment for many patients. Previous study has demonstrated that phosphorylated ERK (pERK) is a key downstream component in the RAF/MEK/ERK signaling pathway. Here, we investigate whether pERK is a useful biomarker for treating HCC with Sorafenib. In vitro cell viability assays showed that the efficacy of Sorafenib was distinctly different according to the level of pERK. Furthermore, in established patient-derived xenografts from HCC specimens, we found that the growth rate of tumors with high levels of pERK was significantly decreased by Sorafenib treatment. Taken together, pERK is a potential biomarker for the sensitivity to Sorafenib in treating HCC.
In hepatocellular carcinoma (HCC), the efficacy of Sorafenib remains moderate and certain patients display a short period of survival following treatment. Our vitro and in vivo results revealed the relationship between the expression of phosphorylated ERK (pERK) and Sorafenib response in HCC. We confirmed that tumors containing higher levels of pERK are more sensitive to Sorafenib. pERK may be a useful biomarker in treating HCC with Sorafenib.
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The role of general psychosocial factors for the use of cancer screening—Findings of a population-based observational study among older adults in Germany
Abstract
Within the framework of the health-belief model, some studies exist investigating the association between illness-specific psychosocial factors and the use of cancer screenings. However, studies investigating the association between general psychosocial factors and the use of cancer screenings are missing. Thus, this study aimed at examining the association between well-established general psychosocial factors and the use of cancer screenings. Data were gathered from a large, population-based sample of community-dwelling individuals aged 40 and above in Germany (n = 7673; in 2014). Loneliness, cognitive well-being, affective well-being (negative and positive affect), optimism, self-efficacy, self-esteem, self-regulation, perceived autonomy, perceived stress, and perceived social exclusion were used as general psychosocial factors. Furthermore, individuals were asked whether they regularly underwent early cancer screening in the past years (yes; no). A total of 65.6% of the individuals used cancer screening. Adjusting for sociodemographic factors, self-rated health, morbidity and lifestyle factors, multiple logistic regressions revealed that the use of cancer screening is positively associated with decreased loneliness, cognitive well-being, optimism, self-efficacy, self-esteem, self-regulation, perceived autonomy, decreased perceived stress, decreased perceived social exclusion, and positive affect, while it is not associated with negative affect. This study stresses the strong association between general psychosocial factors and the use of cancer screening. This knowledge might be fruitful to address individuals at risk for underuse.
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Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib
Abstract
In this study, we determined the gene expression profiles of bone marrow-derived cell fractions, obtained from normal subjects and Chronic Myeloid Leukemia (CML) patients, that were highly enriched for hematopoietic stem (HSCs) and progenitor (HPCs) cells. Our results indicate that the profiles of CML HSCs and HPCs were closer to that of normal progenitors, whereas normal HSCs showed the most different expression profile of all. We found that the expression profiles of HSCs and HPCs from CML marrow were closer to each other than those of HSCs and HPCs from normal marrow. The major biologic processes dysregulated in CML cells included DNA repair, cell cycle, chromosome condensation, cell adhesion, and the immune response. We also determined the genomic changes in both normal and CML progenitor cells under culture conditions, and found that several genes involved in cell cycle, steroid biosynthesis, and chromosome segregation were upregulated, whereas genes involved in transcription regulation and apoptosis were downregulated. Interestingly, these changes were the same, regardless of the addition of Imatinib (IM) to the culture. Finally, we identified three genes—PIEZO2, RXFP1, and MAMDC2- that are preferentially expressed by CML primitive cells and that encode for cell membrane proteins; thus, they could be used as biomarkers for CML stem cells.
Gene expression profiles of hematopoietic stem and progenitor cells from CML patients have been obtained. The in vitro effect of Imatinib on such gene expression profiles was assessed. Potential leukemic biomarker genes were identified.
http://ift.tt/2yKkaIa
Phosphorylated ERK is a potential prognostic biomarker for Sorafenib response in hepatocellular carcinoma
Abstract
Sorafenib, the only approved drug for hepatocellular carcinoma, acts as a remarkable inhibitor of Raf serine-threonine kinases. However, Sorafenib is expensive, and clinical experience shows that it is not an effective treatment for many patients. Previous study has demonstrated that phosphorylated ERK (pERK) is a key downstream component in the RAF/MEK/ERK signaling pathway. Here, we investigate whether pERK is a useful biomarker for treating HCC with Sorafenib. In vitro cell viability assays showed that the efficacy of Sorafenib was distinctly different according to the level of pERK. Furthermore, in established patient-derived xenografts from HCC specimens, we found that the growth rate of tumors with high levels of pERK was significantly decreased by Sorafenib treatment. Taken together, pERK is a potential biomarker for the sensitivity to Sorafenib in treating HCC.
In hepatocellular carcinoma (HCC), the efficacy of Sorafenib remains moderate and certain patients display a short period of survival following treatment. Our vitro and in vivo results revealed the relationship between the expression of phosphorylated ERK (pERK) and Sorafenib response in HCC. We confirmed that tumors containing higher levels of pERK are more sensitive to Sorafenib. pERK may be a useful biomarker in treating HCC with Sorafenib.
http://ift.tt/2hGFUcU
The role of general psychosocial factors for the use of cancer screening—Findings of a population-based observational study among older adults in Germany
Abstract
Within the framework of the health-belief model, some studies exist investigating the association between illness-specific psychosocial factors and the use of cancer screenings. However, studies investigating the association between general psychosocial factors and the use of cancer screenings are missing. Thus, this study aimed at examining the association between well-established general psychosocial factors and the use of cancer screenings. Data were gathered from a large, population-based sample of community-dwelling individuals aged 40 and above in Germany (n = 7673; in 2014). Loneliness, cognitive well-being, affective well-being (negative and positive affect), optimism, self-efficacy, self-esteem, self-regulation, perceived autonomy, perceived stress, and perceived social exclusion were used as general psychosocial factors. Furthermore, individuals were asked whether they regularly underwent early cancer screening in the past years (yes; no). A total of 65.6% of the individuals used cancer screening. Adjusting for sociodemographic factors, self-rated health, morbidity and lifestyle factors, multiple logistic regressions revealed that the use of cancer screening is positively associated with decreased loneliness, cognitive well-being, optimism, self-efficacy, self-esteem, self-regulation, perceived autonomy, decreased perceived stress, decreased perceived social exclusion, and positive affect, while it is not associated with negative affect. This study stresses the strong association between general psychosocial factors and the use of cancer screening. This knowledge might be fruitful to address individuals at risk for underuse.
http://ift.tt/2yKk830
Identification and characterization of a metastatic suppressor BRMS1L as a target gene of p53
Summary
The tumor suppressor p53 and its family members, p63 and p73, play a pivotal role in the cell fate determination in response to diverse upstream signals. As transcription factors, p53 family proteins regulate a number of genes that are involved in cell-cycle arrest, apoptosis, senescence, and maintenance of genomic stability. Recent studies revealed that p53 family proteins are important for the regulation of cell invasion and migration. Microarray analysis showed that breast cancer metastasis-suppressor 1- like (BRMS1L) is upregulated by p53 family proteins, specifically p53, TAp63γ, and TAp73β. We identified two responsive elements of p53 family proteins in the first intron and upstream of BRMS1L. These response elements are well conserved among mammals. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effect. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. Altogether, these results strongly indicate that BRMS1L is one of the mediators downstream of the p53 pathway, and inhibits cancer cell invasion and migration, which are essential steps in cancer metastasis. Collectively, our results demonstrate that BRMS1L is involved in cancer cell invasion and migration, and may be a therapeutic target for cancer.
This article is protected by copyright. All rights reserved.
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Identification and characterization of a metastatic suppressor BRMS1L as a target gene of p53
Summary
The tumor suppressor p53 and its family members, p63 and p73, play a pivotal role in the cell fate determination in response to diverse upstream signals. As transcription factors, p53 family proteins regulate a number of genes that are involved in cell-cycle arrest, apoptosis, senescence, and maintenance of genomic stability. Recent studies revealed that p53 family proteins are important for the regulation of cell invasion and migration. Microarray analysis showed that breast cancer metastasis-suppressor 1- like (BRMS1L) is upregulated by p53 family proteins, specifically p53, TAp63γ, and TAp73β. We identified two responsive elements of p53 family proteins in the first intron and upstream of BRMS1L. These response elements are well conserved among mammals. Functional analysis showed that ectopic expression of BRMS1L inhibited cancer cell invasion and migration; knockdown of BRMS1L by siRNA induced the opposite effect. Importantly, clinical databases revealed that reduced BRMS1L expression correlated with poor prognosis in patients with breast and brain cancer. Altogether, these results strongly indicate that BRMS1L is one of the mediators downstream of the p53 pathway, and inhibits cancer cell invasion and migration, which are essential steps in cancer metastasis. Collectively, our results demonstrate that BRMS1L is involved in cancer cell invasion and migration, and may be a therapeutic target for cancer.
This article is protected by copyright. All rights reserved.
http://ift.tt/2zmKmpa
Halofuginone improves caustic-induced oxidative injury of esophagus in rats
Abstract
Background
The aim of this study is to evaluate the anti-inflammatory and anti-fibrotic effects of halofuginone in caustic esophageal burn injury in rats.
Materials and methods
Corrosive esophageal injury (CEI) was produced in male Wistar albino rats by instilling NaOH solution (1 ml, 37.5%) into the distal esophagus. Rats were decapitated on the 3rd day (early group) or 28th day (late group), and treated daily with either saline or halofuginone (100 µg/kg/day; i.p.), continued on alternate days after the third day. Histopathological evaluation and measurement of nitric oxide (NO), peroxynitrite (ONOO-) and oxygen-derived radicals by chemiluminescence (CL) were made in the distal 2 cm of the esophagus. Non-irrigated proximal esophageal samples were assessed for the levels of nuclear factor (NF)-κB, caspase-3, glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) activity.
Results
GSH, MDA, NF-κB and caspase-3 levels, and MPO activity in the proximal esophagus were not different among groups. Increased number of TUNEL (+) cells in the irrigated esophagus of the early and late caustic injury groups was reduced by halofuginone treatment. High microscopic damage scores in both early and late CEI groups were decreased with halofuginone treatment. NO, ONOO- and CL levels, which were elevated in the saline-treated early CEI group, were reduced by halofuginone treatment, but reduced NO and ONOO- levels in the late period of saline-treated group were increased by halofuginone.
Conclusion
In addition to its anti-fibrotic effects, current findings demonstrate that halofuginone exerts antioxidant and anti-apoptotic actions and supports therapeutic potential for halofuginone in CEI-induced oxidative stress.
http://ift.tt/2iayOBe
Halofuginone improves caustic-induced oxidative injury of esophagus in rats
Abstract
Background
The aim of this study is to evaluate the anti-inflammatory and anti-fibrotic effects of halofuginone in caustic esophageal burn injury in rats.
Materials and methods
Corrosive esophageal injury (CEI) was produced in male Wistar albino rats by instilling NaOH solution (1 ml, 37.5%) into the distal esophagus. Rats were decapitated on the 3rd day (early group) or 28th day (late group), and treated daily with either saline or halofuginone (100 µg/kg/day; i.p.), continued on alternate days after the third day. Histopathological evaluation and measurement of nitric oxide (NO), peroxynitrite (ONOO-) and oxygen-derived radicals by chemiluminescence (CL) were made in the distal 2 cm of the esophagus. Non-irrigated proximal esophageal samples were assessed for the levels of nuclear factor (NF)-κB, caspase-3, glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) activity.
Results
GSH, MDA, NF-κB and caspase-3 levels, and MPO activity in the proximal esophagus were not different among groups. Increased number of TUNEL (+) cells in the irrigated esophagus of the early and late caustic injury groups was reduced by halofuginone treatment. High microscopic damage scores in both early and late CEI groups were decreased with halofuginone treatment. NO, ONOO- and CL levels, which were elevated in the saline-treated early CEI group, were reduced by halofuginone treatment, but reduced NO and ONOO- levels in the late period of saline-treated group were increased by halofuginone.
Conclusion
In addition to its anti-fibrotic effects, current findings demonstrate that halofuginone exerts antioxidant and anti-apoptotic actions and supports therapeutic potential for halofuginone in CEI-induced oxidative stress.
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Neuroendocrine late effects after tailored photon radiotherapy for children with low grade gliomas: Long term correlation with tumour and treatment parameters
To evaluate neuroendocrine late effects in paediatric patients with low grade glioma (LGG) who underwent radiotherapy.
http://ift.tt/2z80zho
A multicentre ‘end to end’ dosimetry audit of motion management (4DCT-defined motion envelope) in radiotherapy
External dosimetry audit is valuable for the assurance of radiotherapy quality. However, motion management has not been rigorously audited, despite its complexity and importance for accuracy. We describe the first end-to-end dosimetry audit for non-SABR (stereotactic ablative body radiotherapy) lung treatments, measuring dose accumulation in a moving target, and assessing adequacy of target dose coverage.
http://ift.tt/2zms3k9
Peri-operative blood transfusion for resected colon cancer: Practice patterns and outcomes in a population-based study
Source:Cancer Epidemiology, Volume 51
Author(s): Sunil V. Patel, Kelly E. Brennan, Sulaiman Nanji, Safiya Karim, Shaila Merchant, Christopher M. Booth
Background & objectivesLiterature suggests that peri-operative blood transfusion among patients with resected colon cancer may be associated with inferior long-term survival. The study objective was to characterize this association in our population.MethodsThis is a retrospective cohort study using the population-based Ontario Cancer Registry (2002–2008). Pathology reports were obtained for a 25% random sample of all cases and constituted the study population. Log binomial regression was used to identify factors associated with transfusion. Cox proportional hazards model explored the association between transfusion and cancer specific survival (CSS) and overall survival (OS).ResultsThe study population included 7198 patients: 18% stage I, 36% stage II, 40% stage III, and 6% stage IV. Twenty-eight percent of patients were transfused. Factors independently associated with transfusion included advanced age (p<0.001), female sex (p<0.001), greater comorbidity (p<0.001), more advanced disease (p<0.001) and open surgical resection (p<0.001). Transfusion was associated with inferior CSS (HR 1.51, 95% CI 1.38–1.65) and OS (HR 1.52, 95% CI 1.41–1.63), after adjusting for important confounders.ConclusionsPeri-operative transfusion rates among patients with colon cancer have decreased over time. Transfusion is associated with inferior long-term CSS and OS.
http://ift.tt/2ibOF2N
Acne in late adolescence is not associated with a raised risk of subsequent malignant melanoma among men
Source:Cancer Epidemiology, Volume 51
Author(s): Teresa Mota Garcia, Ayako Hiyoshi, Ruzan Udumyan, Hugo Sjöqvist, Katja Fall, Scott Montgomery
BackgroundTo evaluate the association of acne in late adolescence with the risk for subsequent malignant melanoma (MM) in men.MethodsSwedish register-based cohort study of 242,096 males born between 1952 and 1956, who took part in compulsory assessments for Swedish military conscription in late adolescence between 1969 and 1975, with subsequent diagnoses of MM (n=1,058) up to December 31, 2009. Covariates included measures of childhood circumstances and information from adolescence on presence of acne, physical fitness, cognitive function, body mass index (BMI), and a summary of diagnoses. Cox regression was used for the analysis.ResultsIn total 1,058 men were diagnosed with MM. Acne was not associated with subsequent MM, with an adjusted hazard ratio (and 95% confidence interval) of 0.95 (0.61 to 1.49). Men with parents who were agricultural workers, and men who lived in northern Sweden, had lower physical fitness, or lower cognitive function had a lower risk of MM. Overweight and obesity was associated with a raised risk, with an adjusted hazard ratio of 1.39 (1.14, 1.71).ConclusionsAcne in late adolescence is unlikely to represent a raised risk for subsequent MM in men. Overweight or obesity was identified as a raised risk for MM, possibly due to the associated increased skin surface area.
http://ift.tt/2gDGOXQ
Methodological issues of assessing the risk of a second cancer occurring in the same site as a first cancer using registry data
Source:Cancer Epidemiology, Volume 51
Author(s): Jérémie Jégu, Marie Moitry, Simona Bara, Brigitte Trétarre, Anne-Valérie Guizard, Anne-Sophie Woronoff, Laetitia Daubisse-Marliac, Véronique Bouvier, Xavier Troussard, Marc Colonna, Delphine Klein, Bénédicte Lapôtre-Ledoux, Michel Velten
ObjectiveTo present methodological issues that can arise with the assessment of the risk of a second primary cancer (SPC) occurring in the same site as a first cancer using registry data.Material and methodsData from ten French cancer registries were used, including data for patients with a first prostate cancer (in males), breast cancer (in females), and colon, lung and kidney cancer (in both sexes) diagnosed between 1989 and 2004. Standardized incidence ratios (SIRs) of SPC were computed by excluding, or not, the risk of an SPC at the same site.ResultsFor prostate cancer, the SIR dropped from 1.11 to 0.72 when the risk of SPC of the prostate was included. SIRs increased from 1.36 to 1.45, from 1.14 to 1.21, from 1.57 to 2.01, and from 1.37 to 1.51 for breast, colon, lung, and kidney respectively.ConclusionThe inclusion, or not, of an SPC at the same site can impact on SPC risk estimates.
http://ift.tt/2iaFwaz
A systematic review of instrumental variable analyses using geographic region as an instrument
Source:Cancer Epidemiology, Volume 51
Author(s): Emily A. Vertosick, Melissa Assel, Andrew J. Vickers
BackgroundInstrumental variables analysis is a methodology to mitigate the effects of measured and unmeasured confounding in observational studies of treatment effects. Geographic area is increasingly used as an instrument.MethodsWe conducted a literature review to determine the properties of geographic area in studies of cancer treatments. We identified cancer studies performed in the United States which incorporated instrumental variable analysis with area-wide treatment rate within a geographic region as the instrument. We assessed the degree of treatment variability between geographic regions, assessed balance of measured confounders afforded by geographic area and compared the results of instrumental variable analysis to those of multivariable methods.ResultsGeographic region as an instrument was relatively common, with 22 eligible studies identified, many of which were published in high-impact journals. Treatment rates did not vary greatly by geographic region. Covariates were not balanced by the instrument in the majority of studies. Eight out of eleven studies found statistically significant effects of treatment on multivariable analysis but not for instrumental variables, with the central estimates of the instrumental variables analysis generally being closer to the null.ConclusionsWe recommend caution and an investigation of IV assumptions when considering the use of geographic region as an instrument in observational studies of cancer treatments. The value of geographic region as an instrument should be critically evaluated in other areas of medicine.
http://ift.tt/2gDwnns
Peri-operative blood transfusion for resected colon cancer: Practice patterns and outcomes in a population-based study
Source:Cancer Epidemiology, Volume 51
Author(s): Sunil V. Patel, Kelly E. Brennan, Sulaiman Nanji, Safiya Karim, Shaila Merchant, Christopher M. Booth
Background & objectivesLiterature suggests that peri-operative blood transfusion among patients with resected colon cancer may be associated with inferior long-term survival. The study objective was to characterize this association in our population.MethodsThis is a retrospective cohort study using the population-based Ontario Cancer Registry (2002–2008). Pathology reports were obtained for a 25% random sample of all cases and constituted the study population. Log binomial regression was used to identify factors associated with transfusion. Cox proportional hazards model explored the association between transfusion and cancer specific survival (CSS) and overall survival (OS).ResultsThe study population included 7198 patients: 18% stage I, 36% stage II, 40% stage III, and 6% stage IV. Twenty-eight percent of patients were transfused. Factors independently associated with transfusion included advanced age (p<0.001), female sex (p<0.001), greater comorbidity (p<0.001), more advanced disease (p<0.001) and open surgical resection (p<0.001). Transfusion was associated with inferior CSS (HR 1.51, 95% CI 1.38–1.65) and OS (HR 1.52, 95% CI 1.41–1.63), after adjusting for important confounders.ConclusionsPeri-operative transfusion rates among patients with colon cancer have decreased over time. Transfusion is associated with inferior long-term CSS and OS.
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Acne in late adolescence is not associated with a raised risk of subsequent malignant melanoma among men
Source:Cancer Epidemiology, Volume 51
Author(s): Teresa Mota Garcia, Ayako Hiyoshi, Ruzan Udumyan, Hugo Sjöqvist, Katja Fall, Scott Montgomery
BackgroundTo evaluate the association of acne in late adolescence with the risk for subsequent malignant melanoma (MM) in men.MethodsSwedish register-based cohort study of 242,096 males born between 1952 and 1956, who took part in compulsory assessments for Swedish military conscription in late adolescence between 1969 and 1975, with subsequent diagnoses of MM (n=1,058) up to December 31, 2009. Covariates included measures of childhood circumstances and information from adolescence on presence of acne, physical fitness, cognitive function, body mass index (BMI), and a summary of diagnoses. Cox regression was used for the analysis.ResultsIn total 1,058 men were diagnosed with MM. Acne was not associated with subsequent MM, with an adjusted hazard ratio (and 95% confidence interval) of 0.95 (0.61 to 1.49). Men with parents who were agricultural workers, and men who lived in northern Sweden, had lower physical fitness, or lower cognitive function had a lower risk of MM. Overweight and obesity was associated with a raised risk, with an adjusted hazard ratio of 1.39 (1.14, 1.71).ConclusionsAcne in late adolescence is unlikely to represent a raised risk for subsequent MM in men. Overweight or obesity was identified as a raised risk for MM, possibly due to the associated increased skin surface area.
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Methodological issues of assessing the risk of a second cancer occurring in the same site as a first cancer using registry data
Source:Cancer Epidemiology, Volume 51
Author(s): Jérémie Jégu, Marie Moitry, Simona Bara, Brigitte Trétarre, Anne-Valérie Guizard, Anne-Sophie Woronoff, Laetitia Daubisse-Marliac, Véronique Bouvier, Xavier Troussard, Marc Colonna, Delphine Klein, Bénédicte Lapôtre-Ledoux, Michel Velten
ObjectiveTo present methodological issues that can arise with the assessment of the risk of a second primary cancer (SPC) occurring in the same site as a first cancer using registry data.Material and methodsData from ten French cancer registries were used, including data for patients with a first prostate cancer (in males), breast cancer (in females), and colon, lung and kidney cancer (in both sexes) diagnosed between 1989 and 2004. Standardized incidence ratios (SIRs) of SPC were computed by excluding, or not, the risk of an SPC at the same site.ResultsFor prostate cancer, the SIR dropped from 1.11 to 0.72 when the risk of SPC of the prostate was included. SIRs increased from 1.36 to 1.45, from 1.14 to 1.21, from 1.57 to 2.01, and from 1.37 to 1.51 for breast, colon, lung, and kidney respectively.ConclusionThe inclusion, or not, of an SPC at the same site can impact on SPC risk estimates.
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A systematic review of instrumental variable analyses using geographic region as an instrument
Source:Cancer Epidemiology, Volume 51
Author(s): Emily A. Vertosick, Melissa Assel, Andrew J. Vickers
BackgroundInstrumental variables analysis is a methodology to mitigate the effects of measured and unmeasured confounding in observational studies of treatment effects. Geographic area is increasingly used as an instrument.MethodsWe conducted a literature review to determine the properties of geographic area in studies of cancer treatments. We identified cancer studies performed in the United States which incorporated instrumental variable analysis with area-wide treatment rate within a geographic region as the instrument. We assessed the degree of treatment variability between geographic regions, assessed balance of measured confounders afforded by geographic area and compared the results of instrumental variable analysis to those of multivariable methods.ResultsGeographic region as an instrument was relatively common, with 22 eligible studies identified, many of which were published in high-impact journals. Treatment rates did not vary greatly by geographic region. Covariates were not balanced by the instrument in the majority of studies. Eight out of eleven studies found statistically significant effects of treatment on multivariable analysis but not for instrumental variables, with the central estimates of the instrumental variables analysis generally being closer to the null.ConclusionsWe recommend caution and an investigation of IV assumptions when considering the use of geographic region as an instrument in observational studies of cancer treatments. The value of geographic region as an instrument should be critically evaluated in other areas of medicine.
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Colchicine is an active treatment for everolimus-induced oral ulcers
Source:European Journal of Cancer
Author(s): Stanislas Ropert, Romain Coriat, Benjamin Verret, Audrey Perret, Francesca Lucibello, Ali N. Chamseddine, Jean-Pierre Armand, Angelo Paci, Olivier Mir
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HMG-CoA reductase inhibition delays DNA repair and promotes senescence after tumor irradiation
Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSBs) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs and success rates of drug development. In a prior screen where we tracked resolution of ionizing radiation-induced foci (IRIF) as a proxy for DSB repair, we had identified pitavastatin (Livalo), an HMG-CoA reductase inhibitor commonly used for lipid lowering, as a candidate radiosensitizer. Here we report that pitavastatin and other lipophilic statins are potent inhibitors of DSB repair in breast and melanoma models both in vitro and in vivo. When combined with ionizing radiation, pitavastatin increased persistent DSBs, induced senescence and enhanced acute effects of radiation on radioresistant melanoma tumors. shRNA knockdown implicated HMG-CoA reductase, farnesyl diphosphate synthase, and protein farnesyl transferase in IRIF resolution, DSB repair and senescence. These data confirm on-target activity of statins, though via inhibition of protein prenylation rather than cholesterol biosynthesis. In light of prior studies demonstrating enhanced efficacy of radiotherapy in patients taking statins, this work argues for clinical evaluation of lipophilic statins as non-toxic radiosensitizers to enhance the benefits of image-guided radiotherapy.
http://ift.tt/2ynbvKi
Pembrolizumab May Be Beneficial in a Subset of Soft-Tissue Sarcomas [Research Watch]
Anti–PD-1 therapy with pembrolizumab achieved responses in 18% of patients with soft-tissue sarcoma.
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Keap1 Loss Drives Kras-Mutant Lung Cancer and Glutaminolysis Dependency [Research Watch]
Loss of Keap1 hyperactivates NRF2 to induce glutaminolysis-dependent Kras-driven lung cancer.
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BRCA1-BARD1 Activates RAD51 for DNA Repair by Homologous Recombination [Research Watch]
BRCA1–BARD1 binds to RAD51 to enhance its activity in the promotion of homologous DNA pairing.
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EGFR Ligands Have Differential Effects on Dimer Stability and Signaling [Research Watch]
EREG and EPGN induce weak EGFR dimerization but sustained signaling compared with EGF.
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Lactate Fuels the TCA Cycle in Non-Small Cell Lung Cancer [Research Watch]
In many patients with NSCLC, lactate is a major fuel source for the tumor TCA cycle.
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HMG-CoA reductase inhibition delays DNA repair and promotes senescence after tumor irradiation
Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSBs) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs and success rates of drug development. In a prior screen where we tracked resolution of ionizing radiation-induced foci (IRIF) as a proxy for DSB repair, we had identified pitavastatin (Livalo), an HMG-CoA reductase inhibitor commonly used for lipid lowering, as a candidate radiosensitizer. Here we report that pitavastatin and other lipophilic statins are potent inhibitors of DSB repair in breast and melanoma models both in vitro and in vivo. When combined with ionizing radiation, pitavastatin increased persistent DSBs, induced senescence and enhanced acute effects of radiation on radioresistant melanoma tumors. shRNA knockdown implicated HMG-CoA reductase, farnesyl diphosphate synthase, and protein farnesyl transferase in IRIF resolution, DSB repair and senescence. These data confirm on-target activity of statins, though via inhibition of protein prenylation rather than cholesterol biosynthesis. In light of prior studies demonstrating enhanced efficacy of radiotherapy in patients taking statins, this work argues for clinical evaluation of lipophilic statins as non-toxic radiosensitizers to enhance the benefits of image-guided radiotherapy.
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The Sunshine ACT And Oncology: Lessons Learned From Urology
Publication date: Available online 13 October 2017
Source:Seminars in Oncology
Author(s): Mahir Maruf, Piyush K. Agarwal, Abhinav Sidana
http://ift.tt/2wUNN50
A prognostic bio-model based on SQSTM1 and N stage identifies nasopharyngeal carcinoma patients at high risk of metastasis for additional induction chemotherapy
Purpose:Metastasis is one of the most important causes of treatment failure in nasopharyngeal carcinoma (NPC). In T4 or N2-3 patients at high risk of metastasis, concurrent chemoradiotherapy (CCRT) is inadequate and additional induction chemotherapy (IC) is controversial. There is a critical need to develop a better patient stratification to efficiently identify patients at high risk of metastasis for additional IC. Recently, Sequestosome 1 (SQSTM1)/p62, an autophagy adaptor protein, was identified as one of the metastasis-related proteins in NPC. However, the mechanism by which SQSTM1 is involved in NPC metastasis was not investigated. Experimental Design:The effect of SQSTM1 on cell migration and invasion was examined in vitro and in vivo. SQSTM1 expression was analyzed in clinical NPC samples using immunohistochemistry (IHC). Luciferase reporter analyses were conducted to identify the effects of SQSTM1 on NF-B transcriptional activity. A prediction bio-model was constructed by Cox analysis. Retrospective and prospective randomized clinical data were adopted to build and test the model, respectively. Results:SQSTM1 mediated epithelial to mesenchymal transition (EMT) through the NF-B pathway to promote NPC metastasis. Inhibiting SQSTM1 enhanced sensitivity to cisplatin in NPC cells. In NPC patients, high SQSTM1 expression was associated with increased risk of distant metastasis. Furthermore, we propose a prognostic bio-model based on SQSTM1 and N stage to predict NPC metastasis. Most importantly, our prospective randomized study suggested that IC is beneficial for NPC patients with high metastasis risk. Conclusions:The prognostic bio-model identifies nasopharyngeal carcinoma patients at high risk of metastasis for additional induction chemotherapy.
http://ift.tt/2yn8h9V
Cell-cycle and DNA-damage response pathway is involved in leptomeningeal metastasis of non-small cell lung cancer
Purpose: Leptomeningeal metastases (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM. Results: The status of EGFR activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA damage response (DDR), suggesting a role of the pathway in LM development. Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need.
http://ift.tt/2ghMfz2
RAD50 expression is associated with poor clinical outcomes after radiotherapy for resected non-small cell lung cancer
Purpose: Although postoperative radiotherapy is often used to maintain local control after surgical resection and chemotherapy for locally advanced non-small cell lung cancer (NSCLC), both locoregional failure and distant metastasis remain problematic. The mechanisms of therapeutic resistance remain poorly understood. Experimental Design: We used reverse-phase protein arrays (RPPAs) to profile the baseline expression of 170 total and phosphorylated proteins in 70 NSCLC cell lines to categorize pathways that may contribute to radiation resistance. Significant markers identified by RPPA were further analyzed in tissue microarrays (TMAs) of specimens from 127 patients with NSCLC who had received surgery before receiving postoperative radiotherapy. Cox regression analysis and log-rank tests were used to identify potential predictive factors. We then validated the biological function of the markers in NSCLC cell lines in vitro. Results: Of the 170 proteins or phospho-proteins profiled, a subset of 12 proteins was found to correlate with radiation response parameters. TMA analysis of the 12 proteins showing the greatest differences in expression in the RPPA analysis demonstrated that RAD50 had the strongest correlation with distant relapse-free survival, locoregional relapse-free survival, and disease-free survival in patients with NSCLC. We confirmed that knockdown of RAD50 sensitized NSCLC cells to radiation and that upregulation of RAD50 increased radioresistance in in vitro experiments. Conclusion: Upregulated RAD50 may be a predictor of radioresistance in patients with lung cancer who received radiotherapy.
http://ift.tt/2ymUn81
Phase 1b/2 Trial of NC-6004 (Nanoparticle Cisplatin) Plus Gemcitabine in Patients with Advanced Solid Tumors
Purpose NC-6004, a novel cisplatin nanoparticle developed using micellar technology exhibits sustained release of cisplatin and selective distribution to tumors. Preclinical data demonstrated a favorable tolerability profile and preserved or improved anti-tumor activity compared to cisplatin across animal models. We evaluated the safety and tolerability of NC-6004 and gemcitabine using a Bayesian continual reassessment model (N-CRM) to determine the optimal dose. Experimental Design Patients with advanced solid tumors received NC-6004 at 60-180mg/m2 on Day 1 and gemcitabine at 1250 mg/m2 on Days 1 and 8 every three weeks. Dose escalation of NC-6004 began with a single patient run-in until a dose limiting toxicity occurred at 180mg/m2. Cohorts of four patients were enrolled at doses predicted by the N-CRM. The maximum tolerated dose (MTD) was defined as having the greatest probability of target toxicity < 25%. Quality of life was assessed using EORTC-QLQ-C30. Results Among 22 patients, the most common Grade 3/4 hematologic adverse events were leukopenia (68%) and thrombocytopenia (59%). Of 20 pretreated patients evaluable for response, half were previously exposed to a platinum agent. The MTD was 135 mg/m2. Nine patients were treated at the MTD with median treatment duration of 15 weeks (range, 3-50). Tumor shrinkage occurred in 11 (55%), partial responses in 3 (15%) and stable disease in 14 (70%). Most patients reported stable or improved EORTC QLQ-C30 scores. Conclusions Greater cisplatin equivalent doses were achieved with no clinically significant neuro-, oto- or nephrotoxicity. These data demonstrate tolerability and promising activity of NC-6004 in combination with gemcitabine.
http://ift.tt/2yiAfBG
A prognostic bio-model based on SQSTM1 and N stage identifies nasopharyngeal carcinoma patients at high risk of metastasis for additional induction chemotherapy
Purpose:Metastasis is one of the most important causes of treatment failure in nasopharyngeal carcinoma (NPC). In T4 or N2-3 patients at high risk of metastasis, concurrent chemoradiotherapy (CCRT) is inadequate and additional induction chemotherapy (IC) is controversial. There is a critical need to develop a better patient stratification to efficiently identify patients at high risk of metastasis for additional IC. Recently, Sequestosome 1 (SQSTM1)/p62, an autophagy adaptor protein, was identified as one of the metastasis-related proteins in NPC. However, the mechanism by which SQSTM1 is involved in NPC metastasis was not investigated. Experimental Design:The effect of SQSTM1 on cell migration and invasion was examined in vitro and in vivo. SQSTM1 expression was analyzed in clinical NPC samples using immunohistochemistry (IHC). Luciferase reporter analyses were conducted to identify the effects of SQSTM1 on NF-B transcriptional activity. A prediction bio-model was constructed by Cox analysis. Retrospective and prospective randomized clinical data were adopted to build and test the model, respectively. Results:SQSTM1 mediated epithelial to mesenchymal transition (EMT) through the NF-B pathway to promote NPC metastasis. Inhibiting SQSTM1 enhanced sensitivity to cisplatin in NPC cells. In NPC patients, high SQSTM1 expression was associated with increased risk of distant metastasis. Furthermore, we propose a prognostic bio-model based on SQSTM1 and N stage to predict NPC metastasis. Most importantly, our prospective randomized study suggested that IC is beneficial for NPC patients with high metastasis risk. Conclusions:The prognostic bio-model identifies nasopharyngeal carcinoma patients at high risk of metastasis for additional induction chemotherapy.
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Cell-cycle and DNA-damage response pathway is involved in leptomeningeal metastasis of non-small cell lung cancer
Purpose: Leptomeningeal metastases (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM. Results: The status of EGFR activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA damage response (DDR), suggesting a role of the pathway in LM development. Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need.
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RAD50 expression is associated with poor clinical outcomes after radiotherapy for resected non-small cell lung cancer
Purpose: Although postoperative radiotherapy is often used to maintain local control after surgical resection and chemotherapy for locally advanced non-small cell lung cancer (NSCLC), both locoregional failure and distant metastasis remain problematic. The mechanisms of therapeutic resistance remain poorly understood. Experimental Design: We used reverse-phase protein arrays (RPPAs) to profile the baseline expression of 170 total and phosphorylated proteins in 70 NSCLC cell lines to categorize pathways that may contribute to radiation resistance. Significant markers identified by RPPA were further analyzed in tissue microarrays (TMAs) of specimens from 127 patients with NSCLC who had received surgery before receiving postoperative radiotherapy. Cox regression analysis and log-rank tests were used to identify potential predictive factors. We then validated the biological function of the markers in NSCLC cell lines in vitro. Results: Of the 170 proteins or phospho-proteins profiled, a subset of 12 proteins was found to correlate with radiation response parameters. TMA analysis of the 12 proteins showing the greatest differences in expression in the RPPA analysis demonstrated that RAD50 had the strongest correlation with distant relapse-free survival, locoregional relapse-free survival, and disease-free survival in patients with NSCLC. We confirmed that knockdown of RAD50 sensitized NSCLC cells to radiation and that upregulation of RAD50 increased radioresistance in in vitro experiments. Conclusion: Upregulated RAD50 may be a predictor of radioresistance in patients with lung cancer who received radiotherapy.
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Phase 1b/2 Trial of NC-6004 (Nanoparticle Cisplatin) Plus Gemcitabine in Patients with Advanced Solid Tumors
Purpose NC-6004, a novel cisplatin nanoparticle developed using micellar technology exhibits sustained release of cisplatin and selective distribution to tumors. Preclinical data demonstrated a favorable tolerability profile and preserved or improved anti-tumor activity compared to cisplatin across animal models. We evaluated the safety and tolerability of NC-6004 and gemcitabine using a Bayesian continual reassessment model (N-CRM) to determine the optimal dose. Experimental Design Patients with advanced solid tumors received NC-6004 at 60-180mg/m2 on Day 1 and gemcitabine at 1250 mg/m2 on Days 1 and 8 every three weeks. Dose escalation of NC-6004 began with a single patient run-in until a dose limiting toxicity occurred at 180mg/m2. Cohorts of four patients were enrolled at doses predicted by the N-CRM. The maximum tolerated dose (MTD) was defined as having the greatest probability of target toxicity < 25%. Quality of life was assessed using EORTC-QLQ-C30. Results Among 22 patients, the most common Grade 3/4 hematologic adverse events were leukopenia (68%) and thrombocytopenia (59%). Of 20 pretreated patients evaluable for response, half were previously exposed to a platinum agent. The MTD was 135 mg/m2. Nine patients were treated at the MTD with median treatment duration of 15 weeks (range, 3-50). Tumor shrinkage occurred in 11 (55%), partial responses in 3 (15%) and stable disease in 14 (70%). Most patients reported stable or improved EORTC QLQ-C30 scores. Conclusions Greater cisplatin equivalent doses were achieved with no clinically significant neuro-, oto- or nephrotoxicity. These data demonstrate tolerability and promising activity of NC-6004 in combination with gemcitabine.
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Emerging roles for long noncoding RNAs in B-cell development and malignancy
Source:Critical Reviews in Oncology/Hematology
Author(s): M. Winkle, J.L. Kluiver, Diepstra Arjan, A. van den Berg
Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation and malignant transformation. LncRNAs have a broad range of possible functions at the transcriptional, posttranscriptional and protein level and their aberrant expression significantly contributes to the hallmarks of cancer cell biology. In addition, their high tissue- and cell-type specificity makes lncRNAs especially interesting as biomarkers, prognostic factors or specific therapeutic targets. Here, we review current knowledge on lncRNA expression changes during normal B-cell development, indicating essential functions in the differentiation process. In addition we address lncRNA deregulation in B-cell malignancies, the putative prognostic value of this as well as the molecular functions of multiple deregulated lncRNAs. Altogether, the discussed work indicates major roles for lncRNAs in normal and malignant B cells affecting oncogenic pathways as well as the response to common therapeutics.
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Emerging roles for long noncoding RNAs in B-cell development and malignancy
Source:Critical Reviews in Oncology/Hematology
Author(s): M. Winkle, J.L. Kluiver, Diepstra Arjan, A. van den Berg
Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation and malignant transformation. LncRNAs have a broad range of possible functions at the transcriptional, posttranscriptional and protein level and their aberrant expression significantly contributes to the hallmarks of cancer cell biology. In addition, their high tissue- and cell-type specificity makes lncRNAs especially interesting as biomarkers, prognostic factors or specific therapeutic targets. Here, we review current knowledge on lncRNA expression changes during normal B-cell development, indicating essential functions in the differentiation process. In addition we address lncRNA deregulation in B-cell malignancies, the putative prognostic value of this as well as the molecular functions of multiple deregulated lncRNAs. Altogether, the discussed work indicates major roles for lncRNAs in normal and malignant B cells affecting oncogenic pathways as well as the response to common therapeutics.
http://ift.tt/2yg9kZT
Routine treatment and outcome of breast cancer in younger versus elderly patients: results from the SENORA project of the prospective German TMK cohort study
Abstract
Purpose
There is an ongoing discussion about 'undertreatment' of breast cancer in elderly patients. Due to low accrual into clinical trials, level 1 evidence is scarce. We report prospective data of elderly patients with breast cancer treated by medical oncologists in Germany.
Methods
The SENORA project within the prospective cohort study TMK (Tumour Registry Breast Cancer) was conducted in 82 centres from 2007–2015. Among 2316 patients, half were enrolled with curative and half with palliative treatment intention. Overall, 478 patients (21%) were aged ≥ 70.
Results
In the adjuvant setting, elderly patients aged ≥ 70 had more advanced tumour stages at diagnosis and a higher prevalence of comorbidities than younger patients. Elderly patients received adjuvant chemotherapy less frequently, yet the 3-year disease-free survival was similar (86% vs. 88%). In the palliative setting, elderly patients more frequently received endocrine therapy and less frequently chemotherapy. Their median overall survival [24.9 months, 95% CI (confidence interval) 20.0–30.2] was significantly shorter than that of younger patients (39.7 months, 95% CI 34.9–44.2). A Cox proportional hazards model showed a significantly increased risk of mortality for: age ≥ 70 at start of therapy, negative HR- or HER2-status, higher number of metastatic sites, more comorbidities and high tumour grading at diagnosis.
Conclusions
Our results shed light on the routine treatment of elderly patients with breast cancer. A regression model demonstrated that age is but one of various prognostic factors determining the shorter overall survival of elderly patients.
http://ift.tt/2gh4ODp
Lacosamide in patients with gliomas and uncontrolled seizures: results from an observational study
Abstract
To report the efficacy and tolerability of lacosamide as an add-on treatment in patients with gliomas and uncontrolled seizures despite conventional antiepileptic drugs (AEDs). We conducted an observational study on 71 patients to describe patterns of response to lacosamide and the association between clinico-pathological factors and seizure control. We observed at 3, 6 and 9 months a seizure reduction ≥ 50% in 74.6, 76 and 86.2% of patients and a seizure freedom in 42.2, 43 and 50%, respectively. The median number of seizures in the 3 months before treatment was 13, and decreased to 3 between baseline and 6 months, and to 0.5 between 6 and 9 months. The best seizure response was observed at 3 months (62%). Sixty per cent of patients displayed the maximum seizure control with doses of lacosamide of 100–250 mg/day, while 21% needed doses up to 400 mg/day. Seizure reduction ≥ 50% and seizure freedom were higher in patients who received lacosamide as first add-on compared to those who received a later adjunctive therapy. A reduction ≥ 50% of seizures was observed in a proportion of patients with progressive disease on MRI. Age > 45 years (OR 0.11, 95% CI 0.02–0.63, p = 0.013) was a significant predictor of seizure freedom at 9 months on multivariate analysis. The study suggests that lacosamide, when added to any baseline AEDs, is effective in obtaining a high seizure reduction and seizure freedom regardless of the tumor activity and response to antineoplastic therapies.
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Lacosamide in patients with gliomas and uncontrolled seizures: results from an observational study
Abstract
To report the efficacy and tolerability of lacosamide as an add-on treatment in patients with gliomas and uncontrolled seizures despite conventional antiepileptic drugs (AEDs). We conducted an observational study on 71 patients to describe patterns of response to lacosamide and the association between clinico-pathological factors and seizure control. We observed at 3, 6 and 9 months a seizure reduction ≥ 50% in 74.6, 76 and 86.2% of patients and a seizure freedom in 42.2, 43 and 50%, respectively. The median number of seizures in the 3 months before treatment was 13, and decreased to 3 between baseline and 6 months, and to 0.5 between 6 and 9 months. The best seizure response was observed at 3 months (62%). Sixty per cent of patients displayed the maximum seizure control with doses of lacosamide of 100–250 mg/day, while 21% needed doses up to 400 mg/day. Seizure reduction ≥ 50% and seizure freedom were higher in patients who received lacosamide as first add-on compared to those who received a later adjunctive therapy. A reduction ≥ 50% of seizures was observed in a proportion of patients with progressive disease on MRI. Age > 45 years (OR 0.11, 95% CI 0.02–0.63, p = 0.013) was a significant predictor of seizure freedom at 9 months on multivariate analysis. The study suggests that lacosamide, when added to any baseline AEDs, is effective in obtaining a high seizure reduction and seizure freedom regardless of the tumor activity and response to antineoplastic therapies.
http://ift.tt/2ymnFmT
Cancers, Vol. 9, Pages 136: Radiation-Induced Changes of microRNA Expression Profiles in Radiosensitive and Radioresistant Leukemia Cell Lines with Different Levels of Chromosome Abnormalities
Cancers, Vol. 9, Pages 136: Radiation-Induced Changes of microRNA Expression Profiles in Radiosensitive and Radioresistant Leukemia Cell Lines with Different Levels of Chromosome Abnormalities
Cancers doi: 10.3390/cancers9100136
Authors: Daria Liamina Wladimir Sibirnyj Anna Khokhlova Viacheslav Saenko Eugenia Rastorgueva Aleksandr Fomin Yury Saenko
In our study, we estimate an effect from chromosome aberrations and genome mutations on changes in microRNA expression profiles in cancer cell lines demonstrating different radiosensitivity. Here, cell viability and microRNA spectrum have been estimated 1, 4, and 24 h after irradiation. MiSeq high-throughput sequencing system (Illumina, San Diego, CA, USA) is employed to perform microRNA spectrum estimation. In the K562 cell line, the number of expressed microRNAs in chromosomes demonstrates a more pronounced variation. An analysis of microRNA effects on signaling pathway activity demonstrates differences in post-transcriptional regulation of the expression of genes included into 40 signaling pathways. In the K562 cell line, microRNA dynamics analyzed for their dependence on chromosome localization show a wider scattering of microRNA expression values for a pair of chromosomes compared to the HL-60 cell line. An analysis of microRNAs expression in the K562 and HL-60 cell lines after irradiation has shown that chromosome abnormalities can affect microRNA expression changes. A study of radiation-induced changes of microRNA expression profiles in the K562 and HL-60 cell lines has revealed a dependence of microRNA expression changes on the number of chromosome aberrations and genome mutations.
http://ift.tt/2zkGRQj
Cancers, Vol. 9, Pages 136: Radiation-Induced Changes of microRNA Expression Profiles in Radiosensitive and Radioresistant Leukemia Cell Lines with Different Levels of Chromosome Abnormalities
Cancers, Vol. 9, Pages 136: Radiation-Induced Changes of microRNA Expression Profiles in Radiosensitive and Radioresistant Leukemia Cell Lines with Different Levels of Chromosome Abnormalities
Cancers doi: 10.3390/cancers9100136
Authors: Daria Liamina Wladimir Sibirnyj Anna Khokhlova Viacheslav Saenko Eugenia Rastorgueva Aleksandr Fomin Yury Saenko
In our study, we estimate an effect from chromosome aberrations and genome mutations on changes in microRNA expression profiles in cancer cell lines demonstrating different radiosensitivity. Here, cell viability and microRNA spectrum have been estimated 1, 4, and 24 h after irradiation. MiSeq high-throughput sequencing system (Illumina, San Diego, CA, USA) is employed to perform microRNA spectrum estimation. In the K562 cell line, the number of expressed microRNAs in chromosomes demonstrates a more pronounced variation. An analysis of microRNA effects on signaling pathway activity demonstrates differences in post-transcriptional regulation of the expression of genes included into 40 signaling pathways. In the K562 cell line, microRNA dynamics analyzed for their dependence on chromosome localization show a wider scattering of microRNA expression values for a pair of chromosomes compared to the HL-60 cell line. An analysis of microRNAs expression in the K562 and HL-60 cell lines after irradiation has shown that chromosome abnormalities can affect microRNA expression changes. A study of radiation-induced changes of microRNA expression profiles in the K562 and HL-60 cell lines has revealed a dependence of microRNA expression changes on the number of chromosome aberrations and genome mutations.
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N - tert -butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors
Abstract
The peptides N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) and BOC-Met-Leu-Phe (BOC1) are widely used antagonists of formyl peptide receptors (FPRs), BOC2 acting as an FPR1/FPR2 antagonist whereas BOC1 inhibits FPR1 only. Extensive investigations have been performed by using these FPR antagonists as a tool to assess the role of FPRs in physiological and pathological conditions. Based on previous observations from our laboratory, we assessed the possibility that BOC2 may exert also a direct inhibitory effect on the angiogenic activity of vascular endothelial growth factor-A (VEGF-A). Our data demonstrate that BOC2, but not BOC1, inhibits the angiogenic activity of heparin-binding VEGF-A165 with no effect on the activity of the non-heparin-binding VEGF-A121 isoform. Endothelial cell-based bioassays, surface plasmon resonance analysis, and computer modeling indicate that BOC2 may interact with the heparin-binding domain of VEGF-A165, thus competing for heparin interaction and preventing the binding of VEGF-A165 to tyrosine kinase receptor VEGFR2, its phosphorylation and downstream signaling. In addition, BOC2 inhibits the interaction of a variety of heparin-binding angiogenic growth factors with heparin, including fibroblast growth factor 2 (FGF2) whose angiogenic activity is blocked by the compound. Accordingly, BOC2 suppresses the angiogenic potential of human tumor cell lines that co-express VEGF-A and FGF2. Thus, BOC2 appears to act as a novel multi-heparin-binding growth factor antagonist. These findings caution about the interpretation of FPR-focusing experimental data obtained with this compound and set the basis for the design of novel BOC2-derived, FPR independent multi-target angiogenesis inhibitors.
http://ift.tt/2xEsaKw
N - tert -butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) inhibits the angiogenic activity of heparin-binding growth factors
Abstract
The peptides N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe (BOC2) and BOC-Met-Leu-Phe (BOC1) are widely used antagonists of formyl peptide receptors (FPRs), BOC2 acting as an FPR1/FPR2 antagonist whereas BOC1 inhibits FPR1 only. Extensive investigations have been performed by using these FPR antagonists as a tool to assess the role of FPRs in physiological and pathological conditions. Based on previous observations from our laboratory, we assessed the possibility that BOC2 may exert also a direct inhibitory effect on the angiogenic activity of vascular endothelial growth factor-A (VEGF-A). Our data demonstrate that BOC2, but not BOC1, inhibits the angiogenic activity of heparin-binding VEGF-A165 with no effect on the activity of the non-heparin-binding VEGF-A121 isoform. Endothelial cell-based bioassays, surface plasmon resonance analysis, and computer modeling indicate that BOC2 may interact with the heparin-binding domain of VEGF-A165, thus competing for heparin interaction and preventing the binding of VEGF-A165 to tyrosine kinase receptor VEGFR2, its phosphorylation and downstream signaling. In addition, BOC2 inhibits the interaction of a variety of heparin-binding angiogenic growth factors with heparin, including fibroblast growth factor 2 (FGF2) whose angiogenic activity is blocked by the compound. Accordingly, BOC2 suppresses the angiogenic potential of human tumor cell lines that co-express VEGF-A and FGF2. Thus, BOC2 appears to act as a novel multi-heparin-binding growth factor antagonist. These findings caution about the interpretation of FPR-focusing experimental data obtained with this compound and set the basis for the design of novel BOC2-derived, FPR independent multi-target angiogenesis inhibitors.
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eHealth literacy, Internet and eHealth service usage: a survey among cancer patients and their relatives
Abstract
Purpose
The aim of our study was to investigate Internet and eHealth usage, with respect to eHealth literacy, by cancer patients and their relatives.
Patients and methods
Using a standardized questionnaire we asked patients who attended lectures on complementary medicine in 2016.
Results
We received 142 questionnaires. The frequency of general Internet usage was directly associated with younger age and better Internet connection. Younger participants were not only more confident in allocating health-related Internet information into reliable or unreliable facts, but also more confident and capable of gaining medical knowledge through eHealth services. A regular use of eHealth services facilitated the decision-making process. Reading ability was associated with a better understanding regarding eHealth offers.
Conclusion
In a modern health care system, emphasis should be on skills contributing to eHealth literacy among patients to improve their ability to profit from eHealth offers and improve health care.
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Disseminated tumor cells are not associated with established risk factors, L1CAM immunoreactivity and outcome in endometrial carcinoma
Abstract
Purpose
The presence of disseminated tumor cells (DTC) in the bone marrow of endometrial carcinoma patients has been demonstrated previously. In contrast to breast cancer, no prognostic significance or association with clinicopathological features was revealed for endometrial carcinoma so far. The aim of this study was to investigate DTC in a large patient cohort with in-depth pathology review data available and to study DTC occurrence in the context of L1CAM and long-term disease specific follow-up.
Methods
Patients treated for endometrial carcinoma at the Tuebingen University Women's hospital between 2003 and 2013 were identified. Cases with previous expert central pathology review including L1CAM immunohistochemistry and bone marrow aspirates available were selected. The presence of DTC and L1CAM expression was studied immunohistochemically.
Results
In 395 cases with a confirmed diagnosis of endometrial carcinoma, bone marrow aspirates were available. DTC were detected in 17.2%. The presence of DTC was independent from tumor histology, grade, lymphovascular space involvement (LVSI), FIGO stage, myoinvasion, L1CAM immunoreactivity, and nodal metastasis. DTC occurred less frequently in cases with a microcystic elongated and fragmented (MELF) pattern of invasion (2.2 vs. 21.8%, p = 0.0003). Disease progression was distributed equally among patients with and without DTC present.
Conclusions
We were able to confirm previous findings of DTC presence in a large well-characterized cohort of endometrial carcinoma patients. DTC are detectable in almost one-fifth of endometrial carcinoma and occur less frequently with a MELF pattern of invasion. Further studies investigating the role of DTC in endometrial carcinoma are warranted.
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Large-scale comprehensive immunohistochemical biomarker analyses in esophageal squamous cell carcinoma
Abstract
Background
Esophageal squamous cell carcinoma (ESCC) is a heterogeneous disease in the sense that the biological behavior is regulated by the activation of various signaling pathways. The aim of this study was to investigate the relationships between the expressions of various targetable proteins and the clinicopathological characteristics of ESCC patients.
Methods
A total of 286 patients with ESCC who had undergone curative surgical resection without neoadjuvant therapy were enrolled in this study. The protein expressions of EGFR, HER2, MET, IGF1R, FGFR2, p53, and PD-L1 were immunohistochemically evaluated in a tissue microarray analysis. The relationships between the expression statuses of each of the above molecules, and the PD-L1 expression status as well as the clinicopathological characteristics, including the survival outcome were assessed.
Results
The expression frequencies of EGFR, HER2, MET, IGF1R, FGFR2, p53, and PD-L1 were as follows: 90.9, 1.0, 2.4, 71.0, 16.1, 62.9 and 23.4%. The overlapping expressions of two or more receptor tyrosine kinases were observed in 72.0%. MET expression was the only poor prognostic factor of recurrence-free survival [hazard ratio (HR) 1.89, 95% confidence interval (CI) 1.15–3.11]; in contrast, PD-L1 was the only favorable prognostic factor for both recurrence-free survival (HR 0.57, 95% CI 0.38–0.87) and overall survival (HR 0.56, 95% CI 0.35–0.89). No correlation was observed between the expressions of PD-L1 and the other molecules.
Conclusions
This large cohort study demonstrated that multiple molecules were co-expressed in most of the ESCC cases, suggesting that combining molecular targeted agents for these co-expressed molecules should be considered.
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Impact of adjuvant chemotherapy after neoadjuvant radio- or radiochemotherapy for patients with locally advanced rectal cancer
Abstract
Background
Due to its primarily extraperitoneal location, potential affection of the anorectal continence and different metastatic behavior the rectal carcinoma (RC) is classified and treated as an independent disease. Over the past few decades various trials have led to improved multimodal therapies (including radiation, chemotherapy and surgery) for locally advanced rectal cancer and significant changes in the management of this disease whereas the benefit of adjuvant chemotherapy remains unclear.
Methods
Based on a prospective tumor register of the University Hospital of Wuerzburg data of 263 patients having undergone neoadjuvant therapy and surgical resection for locally advanced rectal cancer were retrieved from the Wuerzburg International database (WID) between October 1992 and September 2013 analyzing the overall survival according to the application of an adjuvant therapy.
Results
The cohort consisted of 263 patients with a median age of 65 years (27–89 years), mostly male gender (n = 191; 72.6%) and an ASA performance score of II or III. 143 patients (54.3%) received an adjuvant therapy. Those patients have been significant younger (median 10 years; p < 0.05) and in a better general condition (ASA-score; p < 0.05). The tumor specific overall survival of adjuvant treated patients was significant better (5-years overall-survival 87.4%; p = 0.025) than the surveillance group. In the performed subgroup analysis no significant differences in overall survival according to the kind of neoadjuvant therapy (radiation vs. radiochemotherapy) have been found whereas patients in lower UICC-stages (ypUICC 0 + I) had a significant benefit by receiving a postoperative chemotherapy (p = 0.035).
Conclusion
We considered patients with locally advanced rectal cancer have a significant benefit in overall survival by receiving an adjuvant chemotherapy especially in lower pathological tumor stage (ypUICC 0 + I). Especially because of the heterogeneity of our study population prospective randomized trials are necessary to determine the impact of adjuvant chemotherapy for locally advanced rectal cancer.
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Overexpression of glutathione peroxidase 1 predicts poor prognosis in oral squamous cell carcinoma
Abstract
Purpose
Intracellular antioxidant enzymes are commonly upregulated in various cancer types and are associated with treatment outcomes. Because the relationship has rarely been examined in oral squamous cell carcinoma (OSCC), we aimed to evaluate the association between the levels of glutathione peroxidase (GPX)1, GPX4, and thioredoxin reductase (TrxR)1 expression and prognosis in patients with OSCC who underwent curative surgical resection.
Methods
This study included 233 patients who underwent curative surgery for previously untreated OSCC between 2000 and 2012. Tumour GPX1, GPX4, and TrxR1 expression was evaluated by immunohistochemistry and was dichotomised to low and high values according to defined expression levels. The association between GPX1, GPX4, and TrxR1 expression and clinicopathological results was analysed. Univariate and multivariate analyses using the Cox proportional hazards model were conducted to assess the significance of differences in recurrence or survival outcomes between variables.
Results
High GPX1, GPX4, and TrxR1 expression was observed in 99 (42.5%), 133 (57.1%), and 46 (19.7%) patients, respectively. GPX1 overexpression was significantly correlated with nodal metastasis, advanced overall stage, depth of invasion of >10 mm, high grade and perineural invasion (P < 0.05). High GPX4 expression was also related to nodal metastasis, overall advanced stage and high grade (P < 0.05). Univariate and multivariate analyses showed that increased GPX1 expression was significantly associated with poor disease-free, cancer-specific and overall survival (all P < 0.05), while increased GPX4 or TrxR1 expression was not (all P > 0.1).
Conclusions
Tumour GPX1 expression is a useful biomarker predictive of recurrence and survival in OSCC patients.
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Clinical utility of a blood-based protein assay to increase screening of elevated-risk patients for colorectal cancer in the primary care setting
Abstract
Purpose
Colorectal cancer (CRC) screening is effective in finding early stage CRC and dramatically improves survival rates. Despite this, the number of eligible patients who do not obtain CRC screening is unacceptably high.
Methods
We conducted a longitudinal, randomized controlled trial investigating the utility of a blood-based protein assay on the quality of care delivered by practicing PCPs in the United States. We used standardized simulated patients (CPVs), presenting with symptoms suggestive of a higher likelihood of CRC, to measure how frequently these PCPs ordered diagnostic colonoscopy. 190 PCPs cared for three patients at baseline and three patients post-intervention. The PCPs were randomized into one of two study arms: control and intervention. The intervention arm consisted of educational materials about the blood-based protein assay and positive test results. Each simulated patient in the intervention arm had a positive test result that was given to the doctor. The controls were given neither intervention materials nor blood-based protein assay results. Physician responses in both groups were scored against evidence-based criteria. Data were collected at baseline and post-intervention.
Results
At baseline, we found that 71% of physicians ordered diagnostic colonoscopy. In round 2, 23% of physicians in the intervention arm adopted the new blood-based protein assay. Ordering physicians were 3.88 (95% CI 1.67–9.03) times more likely to order a diagnostic colonoscopy. In percentage terms, those who ordered the assay were more likely to order colonoscopy (92%) than either intervention physicians who did not order the assay (77%) or control physicians (66%) (p < 0.001). A marginal effects estimation showed that use of the assay would increase ordering colonoscopy to nearly 95%.
Conclusion
Over one-third of adults in the United States do not follow the recommended screening guidelines for CRC. The introduction of a blood-based protein assay significantly increased the likelihood that physicians would order diagnostic colonoscopies in elevated-risk patients compared to those without access to the assay results. The overall change in clinical utility observed here has the potential to significantly improve clinical care.
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All-treatment array of hepatocellular carcinoma from initial diagnosis to death: observation of cumulative treatments
Abstract
Purpose
In clinical practice, most patients with hepatocellular carcinoma require subsequent treatments for remaining, progressing, or recurring tumors. We investigated all-treatment array and outcomes in an HCC cohort from initial diagnosis to death.
Methods
We enrolled 1687 consecutive patients with HCC who underwent initial diagnosis and treatment at the National Cancer Center, Korea, from January 2004 to December 2009.
Results
In total, 1357 patients (80.4%) showed RPRTs during median 20.4-month follow-up. Initial transplantation resulted in the least rate (32.3%) of RPRTs. Median treatment frequency was 3.0 times (range 1–20) and 382 patients (27.3%) received treatments ≥6 times. The median treatment frequency was different based on four factors (p < 0.05): age, tumor stage, tumor type and initial treatment modality. Patients with Barcelona Clinic Liver Cancer stage 0 received less frequent treatments. As the stage progressed from 0 to B, the median treatment frequency increased. Radiofrequency ablation as initial treatment was associated with the longest median treatment interval at 19.0 weeks, followed by resection at 14.1 weeks. The median treatment interval was significantly shorter as the stage progressed (p < 0.01). TACE was most frequently performed for RPRTs; the median number of subsequent TACE was 3 (range 1–19). Subsequent treatment array was very heterogeneous, and no certain pattern was found.
Conclusions
Our findings suggest that the survival outcome of patients with HCC is based on the results of cumulative multiple treatments rather than an initial treatment. It is time to consider prospective studies evaluating sequential treatment array of HCC.
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Unmonitored use of herbal medicine by patients with breast cancer: reframing expectations
Abstract
Purpose
To identify the unmonitored use of herbal medicine by female patients with breast cancer, examining the impact of an integrative physician (IP) consultation on this practice.
Methods
The files of 269 female patients with breast cancer following an IP consultation were surveyed retrospectively for use of herbal medicine for cancer-related goals. Expectations from the IP consultation and adherence to the IP-guided treatments were examined as well.
Results
Among the cohort, 111 (41.3%) reported using herbal medicine for cancer-related goals, unmonitored by their oncology healthcare professional. Factors predicting herbal medicine use were the adoption of dietary changes (odds ratio = 13.6, p < 0.001, CI 7.16–26.0) and the expectation that the IP consultation and treatments would address cancer-related goals (odds ratio = 3.29, p = 0.001, CI 1.64–6.6). Patients with metastatic disease were more likely to be using herbal medicine than non-users (34.5 vs. 22.8%; p = 0.088), as were those who had consulted with a complementary/alternative medicine practitioner (54.9 vs. 20.8%; p = 0.005). The IP advised 17 patients (15.3%) to stop taking specific herbal products due to safety-related concerns; and 10 patients to take dietary supplements for relief of specific symptoms. Herbal medicine users were less likely than non-users to adhere to the IP-recommended treatment program (34.7 vs. 48.3%; p = 0.037).
Conclusions
Unmonitored use of herbal medicine by patients with breast cancer is more frequent among those adopting dietary changes for cancer-related goals. Integrative physicians provide evidence-based guidance on the safe and effective use of herbal products, and reframe patient expectations from cancer-related goals to reducing symptoms and improving quality of life.
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Spectrophotometric photodynamic detection involving extracorporeal treatment with hexaminolevulinate for bladder cancer cells in voided urine
Abstract
Purpose
To evaluate the feasibility of hexaminolevulinate (HAL) for the photodynamic detection of cancer cells in voided urine.
Methods
This study included 50 patients with bladder cancer that was confirmed histologically after transurethral resection (bladder cancer group) and 50 outpatients without a history of urothelial carcinoma or cancer-related findings (no malignancy group). One third of the voided urine samples were incubated with aminolevulinic acid (ALA-treated samples), one third were incubated with HAL (HAL-treated samples), and the remaining samples were incubated without treatment (untreated samples). For detecting cellular protoporphyrin IX levels, the intensity of the samples at the excitation wavelength of 405 nm was measured using a spectrophotometer. The difference between the intensity of the ALA-treated or HAL-treated samples and the untreated samples at 635 nm was calculated.
Results
HAL-induced fluorescence cytology (HFC) showed that the difference was significantly higher in patients with high-grade tumors than in those with low-grade tumors (p = 0.0003) and the difference was significantly higher in patients with low-grade tumors than in those without a history of urothelial carcinoma or cancer-related findings (p = 0.021). The areas under the receiver operating characteristic curves of ALA-induced fluorescence cytology (AFC) and HFC were 0.77 and 0.81, respectively. The AUC of HFC was significantly higher than that of AFC (p < 0.0001). The overall sensitivity values for conventional cytology, AFC, and HFC were 49, 74, and 74%, respectively. The overall specificity values for AFC and HFC were 70 and 94%, respectively.
Conclusions
Spectrophotometric photodynamic detection involving extracorporeal treatment with HAL for bladder cancer cells in voided urine showed high accuracy. This bladder cancer detection method is easy and cost-effective, and has the potential for clinical use.
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EZH2 is involved in silencing of WNT5A during epithelial–mesenchymal transition of colon cancer cell line
Abstract
Purpose
Transforming growth factor-β (TGF-β) induction of epithelial–mesenchymal transition (EMT) in SW480 was established as a system for studies of colon cancer metastasis. However, the epigenetic mechanisms underlying this process remain unknown. In mammal, polycomb repressive complex-2 (PRC2) is a highly conserved histone methyltransferase involved in epigenetic regulations. Enhancer of zeste Homolog 2 (EZH2) is the catalytic subunit of PRC2, which catalyzes methylation of lysine 27 of histone H3 (H3K27).
Methods
An inducible EMT system in colorectal cancer was utilized to study its mechanistic and phenotypic changes. Particularly, gene expression analysis was studied after immunoprecipitation.
Results
In this study, we reported that EZH2 is significantly enriched in the promoter region of WNT5A after TGF-β induction in SW480 colon cancer cell line, which in turn silenced the expression of WNT5A. Furthermore, EZH2 inhibitor antagonized the TGF-β-induced morphological conversion associated with epithelial–mesenchymal transition (EMT). Conversely, inhibition of histone H3K27me3 reader CBX does not affect the WNT5A expression level during TGF-β-induced EMT.
Conclusions
Our results indicate that EZH2 was essential for the silencing of WNT5A during TGF-β-induced epithelial–mesenchymal transition of colon cancer cells.
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A novel interplay between HOTAIR and DNA methylation in osteosarcoma cells indicates a new therapeutic strategy
Abstract
Purpose
Osteosarcoma (OS) is one of the most prevalent primary malignant bone tumors in adolescent. HOTAIR is highly expressed and associated with the epigenetic modifications, especially DNA methylation, in cancer. However, the regulation mechanism between HOTAIR and DNA methylation and the biological effects of them in the pathogenesis of osteosarcoma remains elusive.
Method
Through RNA-sequencing and computational analysis, followed by a variety of experimental validations, we report a novel interplay between HOTAIR, miR-126, and DNA methylation in OS.
Results
We found that HOTAIR is highly expressed in OS cells and the knockdown of HOTAIR leads to the down-regulation of DNMT1, as well as the decrease of global DNA methylation level. RNA-sequencing analysis of HOTAIR-regulated gene shows that CDKN2A is significantly repressed by HOTAIR. A series of experiments show that HOTAIR represses the expression of CDKN2A through inhibiting the promoter activity of CDKN2A by DNA hypermethylation. Further evidence shows that HOTAIR activates the expression of DNMT1 through repressing miR-126, which is the negative regulator of DNMT1. Functionally, HOTAIR depletion increases the sensibility of OS cells to DNMT1 inhibitor through regulating the viability and apoptosis of OS cells via HOTAIR-miR126-DNMT1-CDKN2A axis.
Conclusion
These results not only enrich our understanding of the regulation relationship between non-coding RNA, DNA methylation, and gene expression, however, also provide a novel direction in developing more sophisticated therapeutic strategies for OS patients.
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Opa interacting protein 5 acts as an oncogene in bladder cancer
Abstract
Purpose
To explore the biological functions and mechanism of Opa interacting protein 5 (OIP5) in bladder cancer (BC).
Methods
We investigated the expression of OIP5 in BC through immunohistochemical staining (IHC) and its correlation with clinicopathologic features of BC patients. Moreover, knockdown of OIP5 was performed in BC cell lines and colony formation capacity, cell growth curve, cell cycle phase and cell apoptosis assay was applied for investigating the roles of OIP5 in BC. Moreover, the expression of OIP5 was validated through the Cancer Genome Atlas (TCGA) database. The diagnosis value of OIP5 was accessed by receiver operating characteristic (ROC) analysis in TCGA database.
Results
The expression of OIP5 in BC tissues was significantly higher than that in adjacent non-tumor tissues and bladder mucosa tissues with chronic cystitis. Higher protein expression level of OIP5 predicted shorter survival time in patients with BC, which was significantly correlated with larger tumor size, high-grade tumor and advanced T classification. The expression of OIP5 was considerably decreased after lentivirus infection both at mRNA and protein levels. Functional assay displayed that silencing of OIP5 inhibited colony formation capacity and cell growth in BC cell lines. Cell cycle assays indicated that suppressed OIP5 disturbed the balance of the cell cycle in BC cell lines, which increased the cell population of the G1 phase and decreased the cell population of the S phase. Furthermore, knockdown of OIP5 expression enhanced cell apoptosis process. The expression of OIP5 was significantly up-regulated in BC compared with adjacent non-tumor tissues based on TCGA database. OIP5 had the potential diagnostic value for BC.
Conclusions
Our work demonstrated that OIP5 might function as an oncogene to promote colony formation capacity and cell growth, arrest cell cycle and suppress cell apoptosis in bladder cancer.
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Overexpression of glutathione peroxidase 1 predicts poor prognosis in oral squamous cell carcinoma
Abstract
Purpose
Intracellular antioxidant enzymes are commonly upregulated in various cancer types and are associated with treatment outcomes. Because the relationship has rarely been examined in oral squamous cell carcinoma (OSCC), we aimed to evaluate the association between the levels of glutathione peroxidase (GPX)1, GPX4, and thioredoxin reductase (TrxR)1 expression and prognosis in patients with OSCC who underwent curative surgical resection.
Methods
This study included 233 patients who underwent curative surgery for previously untreated OSCC between 2000 and 2012. Tumour GPX1, GPX4, and TrxR1 expression was evaluated by immunohistochemistry and was dichotomised to low and high values according to defined expression levels. The association between GPX1, GPX4, and TrxR1 expression and clinicopathological results was analysed. Univariate and multivariate analyses using the Cox proportional hazards model were conducted to assess the significance of differences in recurrence or survival outcomes between variables.
Results
High GPX1, GPX4, and TrxR1 expression was observed in 99 (42.5%), 133 (57.1%), and 46 (19.7%) patients, respectively. GPX1 overexpression was significantly correlated with nodal metastasis, advanced overall stage, depth of invasion of >10 mm, high grade and perineural invasion (P < 0.05). High GPX4 expression was also related to nodal metastasis, overall advanced stage and high grade (P < 0.05). Univariate and multivariate analyses showed that increased GPX1 expression was significantly associated with poor disease-free, cancer-specific and overall survival (all P < 0.05), while increased GPX4 or TrxR1 expression was not (all P > 0.1).
Conclusions
Tumour GPX1 expression is a useful biomarker predictive of recurrence and survival in OSCC patients.
http://ift.tt/2xDIEmc
eHealth literacy, Internet and eHealth service usage: a survey among cancer patients and their relatives
Abstract
Purpose
The aim of our study was to investigate Internet and eHealth usage, with respect to eHealth literacy, by cancer patients and their relatives.
Patients and methods
Using a standardized questionnaire we asked patients who attended lectures on complementary medicine in 2016.
Results
We received 142 questionnaires. The frequency of general Internet usage was directly associated with younger age and better Internet connection. Younger participants were not only more confident in allocating health-related Internet information into reliable or unreliable facts, but also more confident and capable of gaining medical knowledge through eHealth services. A regular use of eHealth services facilitated the decision-making process. Reading ability was associated with a better understanding regarding eHealth offers.
Conclusion
In a modern health care system, emphasis should be on skills contributing to eHealth literacy among patients to improve their ability to profit from eHealth offers and improve health care.
http://ift.tt/2xDIKdy
Disseminated tumor cells are not associated with established risk factors, L1CAM immunoreactivity and outcome in endometrial carcinoma
Abstract
Purpose
The presence of disseminated tumor cells (DTC) in the bone marrow of endometrial carcinoma patients has been demonstrated previously. In contrast to breast cancer, no prognostic significance or association with clinicopathological features was revealed for endometrial carcinoma so far. The aim of this study was to investigate DTC in a large patient cohort with in-depth pathology review data available and to study DTC occurrence in the context of L1CAM and long-term disease specific follow-up.
Methods
Patients treated for endometrial carcinoma at the Tuebingen University Women's hospital between 2003 and 2013 were identified. Cases with previous expert central pathology review including L1CAM immunohistochemistry and bone marrow aspirates available were selected. The presence of DTC and L1CAM expression was studied immunohistochemically.
Results
In 395 cases with a confirmed diagnosis of endometrial carcinoma, bone marrow aspirates were available. DTC were detected in 17.2%. The presence of DTC was independent from tumor histology, grade, lymphovascular space involvement (LVSI), FIGO stage, myoinvasion, L1CAM immunoreactivity, and nodal metastasis. DTC occurred less frequently in cases with a microcystic elongated and fragmented (MELF) pattern of invasion (2.2 vs. 21.8%, p = 0.0003). Disease progression was distributed equally among patients with and without DTC present.
Conclusions
We were able to confirm previous findings of DTC presence in a large well-characterized cohort of endometrial carcinoma patients. DTC are detectable in almost one-fifth of endometrial carcinoma and occur less frequently with a MELF pattern of invasion. Further studies investigating the role of DTC in endometrial carcinoma are warranted.
http://ift.tt/2kNFcPM
Large-scale comprehensive immunohistochemical biomarker analyses in esophageal squamous cell carcinoma
Abstract
Background
Esophageal squamous cell carcinoma (ESCC) is a heterogeneous disease in the sense that the biological behavior is regulated by the activation of various signaling pathways. The aim of this study was to investigate the relationships between the expressions of various targetable proteins and the clinicopathological characteristics of ESCC patients.
Methods
A total of 286 patients with ESCC who had undergone curative surgical resection without neoadjuvant therapy were enrolled in this study. The protein expressions of EGFR, HER2, MET, IGF1R, FGFR2, p53, and PD-L1 were immunohistochemically evaluated in a tissue microarray analysis. The relationships between the expression statuses of each of the above molecules, and the PD-L1 expression status as well as the clinicopathological characteristics, including the survival outcome were assessed.
Results
The expression frequencies of EGFR, HER2, MET, IGF1R, FGFR2, p53, and PD-L1 were as follows: 90.9, 1.0, 2.4, 71.0, 16.1, 62.9 and 23.4%. The overlapping expressions of two or more receptor tyrosine kinases were observed in 72.0%. MET expression was the only poor prognostic factor of recurrence-free survival [hazard ratio (HR) 1.89, 95% confidence interval (CI) 1.15–3.11]; in contrast, PD-L1 was the only favorable prognostic factor for both recurrence-free survival (HR 0.57, 95% CI 0.38–0.87) and overall survival (HR 0.56, 95% CI 0.35–0.89). No correlation was observed between the expressions of PD-L1 and the other molecules.
Conclusions
This large cohort study demonstrated that multiple molecules were co-expressed in most of the ESCC cases, suggesting that combining molecular targeted agents for these co-expressed molecules should be considered.
http://ift.tt/2xE817B
Impact of adjuvant chemotherapy after neoadjuvant radio- or radiochemotherapy for patients with locally advanced rectal cancer
Abstract
Background
Due to its primarily extraperitoneal location, potential affection of the anorectal continence and different metastatic behavior the rectal carcinoma (RC) is classified and treated as an independent disease. Over the past few decades various trials have led to improved multimodal therapies (including radiation, chemotherapy and surgery) for locally advanced rectal cancer and significant changes in the management of this disease whereas the benefit of adjuvant chemotherapy remains unclear.
Methods
Based on a prospective tumor register of the University Hospital of Wuerzburg data of 263 patients having undergone neoadjuvant therapy and surgical resection for locally advanced rectal cancer were retrieved from the Wuerzburg International database (WID) between October 1992 and September 2013 analyzing the overall survival according to the application of an adjuvant therapy.
Results
The cohort consisted of 263 patients with a median age of 65 years (27–89 years), mostly male gender (n = 191; 72.6%) and an ASA performance score of II or III. 143 patients (54.3%) received an adjuvant therapy. Those patients have been significant younger (median 10 years; p < 0.05) and in a better general condition (ASA-score; p < 0.05). The tumor specific overall survival of adjuvant treated patients was significant better (5-years overall-survival 87.4%; p = 0.025) than the surveillance group. In the performed subgroup analysis no significant differences in overall survival according to the kind of neoadjuvant therapy (radiation vs. radiochemotherapy) have been found whereas patients in lower UICC-stages (ypUICC 0 + I) had a significant benefit by receiving a postoperative chemotherapy (p = 0.035).
Conclusion
We considered patients with locally advanced rectal cancer have a significant benefit in overall survival by receiving an adjuvant chemotherapy especially in lower pathological tumor stage (ypUICC 0 + I). Especially because of the heterogeneity of our study population prospective randomized trials are necessary to determine the impact of adjuvant chemotherapy for locally advanced rectal cancer.
http://ift.tt/2kQ3QQb
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