Current treatment for acute myeloid leukemia (AML) is less than optimal, but increased understanding of disease pathobiology and genomics has led to clinical investigation of novel targeted therapies and ratio...
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 22 Φεβρουαρίου 2018
CDK9 inhibitors in acute myeloid leukemia
Establishment and characterization of in vivo orthotopic bioluminescent xenograft models from human osteosarcoma cell lines in Swiss nude and NSG mice
Abstract
Osteosarcoma is one of the most common primary bone tumors in childhood and adolescence. Metastases occurrence at diagnosis or during disease evolution is the main therapeutic challenge. New drug evaluation to improve patient survival requires the development of various preclinical models mimicking at best the complexity of the disease and its metastatic potential. We describe here the development and characteristics of two orthotopic bioluminescent (Luc/mKate2) cell-derived xenograft (CDX) models, Saos-2-B-Luc/mKate2-CDX and HOS-Luc/mKate2-CDX, in different immune (nude and NSG mouse strains) and bone (intratibial and paratibial with periosteum activation) contexts. IVIS SpectrumCT system allowed both longitudinal computed tomography (CT) and bioluminescence real-time follow-up of primary tumor growth and metastatic spread, which was confirmed by histology. The murine immune context influenced tumor engraftment, primary tumor growth, and metastatic spread to lungs, bone, and spleen (an unusual localization in humans). Engraftment in NSG mice was found superior to that found in nude mice and intratibial bone environment more favorable to engraftment compared to paratibial injection. The genetic background of the two CDX models also led to distinct primary tumor behavior observed on CT scan. Saos-2-B-Luc/mKate2-CDX showed osteocondensed, HOS-Luc/mKate2-CDX osteolytic morphology. Bioluminescence defined a faster growth of the primary tumor and metastases in Saos-2-B-Luc/mKate2-CDX than in HOS-Luc/mKate2-CDX. The early detection of primary tumor growth and metastatic spread by bioluminescence allows an improved exploration of osteosarcoma disease at tumor progression, and metastatic spread, as well as the evaluations of anticancer treatments. Our orthotopic models with metastatic spread bring complementary information to other types of existing osteosarcoma models.
New osteosarcoma preclinical models in an orthotropic bone setting with the possibility to follow in vivo both primary tumor growth and metastatic spread will further help testing and development of new drug in this disease which outcome has not improved since several decades.
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LncRNA HOTAIR influences cell growth, migration, invasion, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer
Abstract
To study the regulatory effect of lncRNA HOTAIR/miR-20a-5p/HMGA2 axis on breast cancer (BC) cell growth, cell mobility, invasiveness, and apoptosis. The microarray data of lncRNAs and mRNAs with differential expression in BC tissues were analyzed in the Cancer Genome Atlas (TCGA) database. LncRNA HOX transcript antisense RNA (lncRNA HOTAIR) expression in BC was assessed by qRT-PCR. Cell viability was confirmed using MTT and colony formation assay. Cell apoptosis was analyzed by TdT-mediated dUTP nick-end labeling (TUNEL) assay. Cell mobility and invasiveness were testified by transwell assay. RNA pull-down and dual luciferase assay were used for analysis of the correlation between lncRNA HOTAIR and miR-20a-5p, as well as relationship of miR-20a-5p with high mobility group AT-hook 2 (HMGA2). Tumor xenograft study was applied to confirm the correlation of lncRNA HOTAIR/miR-20a-5p/HMGA2 axis on BC development in vivo. The expression levels of the lncRNA HOTAIR were upregulated in BC tissues and cells. Knockdown lncRNA HOTAIR inhibited cell propagation and metastasis and facilitated cell apoptosis. MiR-20a-5p was a target of lncRNA HOTAIR and had a negative correlation with lncRNA HOTAIR. MiR-20a-5p overexpression in BC suppressed cell growth, mobility, and invasiveness and facilitated apoptosis. HMGA2 was a target of miR-20a-5p, which significantly induced carcinogenesis of BC. BC cells progression was mediated by lncRNA HOTAIR via affecting miR-20a-5p/HMGA2 in vivo. LncRNA HOTAIR affected cell growth, metastasis, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer.
The expression levels of the lncRNA HOTAIR were upregulated in BC tissues and cells. Knockdown lncRNA HOTAIR inhibited cell propagation and metastasis and facilitated cell apoptosis. LncRNA HOTAIR affected cell growth, metastasis, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer.
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Prognostic variables for temporal lobe injury after intensity modulated-radiotherapy of nasopharyngeal carcinoma
Abstract
To determine predictive factors for temporal lobe injury (TLI) in nasopharyngeal carcinoma patient (NPC) treated with intensity-modulated radiation therapy (IMRT). A total of 695 NPC cases treated with IMRT were retrospectively analyzed. TLI was diagnosed on MRI images. Volume-dose histograms for 870 evaluable temporal lobes were analyzed, and the predictive factors for the occurrence of TLI was evaluated. Receiver operating characteristic curve (ROC) and Logistic regression analysis was used to determine volume-dose parameters that predict temporal lobe injury (TLI). Univariate and multivariate analysis were used to analyze the predictive factors for TLI. The radiation dose-tolerance model of temporal lobe was calculated by logistic dose-response model. The median follow-up time was 73 months. A total of 8.5% patients were diagnosed with TLI. Among all the volume-dose parameters, logistic regression model showed D2cc (the dose Gray delivered to 2 cubic centimeter volume) was an only independent predictive factor. Multivariate analysis showed D2cc of temporal lobe, fraction size of prescription, T stage, and chemotherapy were the independent predictive factors for TLI. Logistic dose-response model has indicated the TD5/5 and TD50/5 of D2cc are 60.3 Gy and 76.9 Gy, respectively. D2cc of temporal lobe, fraction size of prescription, T stage, and chemotherapy were the possible independent predictive factors for TLI after IMRT of NPC. Biologic effective doses (TD5/5 and TD50/5) of D2cc are considered to prevent TLI.
A total of 695 NPC cases treated with IMRT were retrospectively analyzed with the radiation-induced temporal lobe injury on MRI images. D2cc of temporal lobe, fraction size of prescription, T stage, and chemotherapy were the possible independent predictive factors for TLI after IMRT of NPC. Biologic effective doses (TD5/5 and TD50/5) of D2cc are considered to prevent TLI.
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CGB5 expression is independently associated with poor overall survival and recurrence-free survival in patients with advanced gastric cancer
Abstract
The human CGB5 gene encodes chorionic gonadotropin (hCG)β 5, which is aberrantly expressed in trophoblastic neoplasm and in some non-trophoblastic neoplasms. Fucntional studies observed that it involved tumor initiation, growth, and metastatic outgrowth. In this study, using data from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD), we assessed the independent prognostic value of CGB5 expression in patients with primary gastric cancer (GC). Results showed that CGB5 expression was nearly not expressed in normal GC tissues. In comparison, its expression was detected in 214 of the 415 primary GC cases (51.6%) in TCGA-STAD and was associated with poor response to primary therapy and a higher risk of recurrence and death. In early stages, CGB5 expression was not a prognostic factor in terms of OS (HR: 1.448; 95% CI: 0.811–2.588, P = 0.211) or RFS (HR: 1.659; 95% CI: 0.778–3.540, P = 0.190). However, its expression was independently associated with unfavorable OS (HR: 1.719; 95% CI: 1.115–2.651, P = 0.014) and RFS (HR: 3.602; 95% CI: 1.708–7.598, P = 0.001) in advanced stages. Using deep sequencing data from TCGA-STAD, we found that CGB5 expression was not related to its genetic amplification or DNA methylation in GC. Based on these findings, we infer that CGB5 expression is common in GC patients and its expression might independently predict poor OS and RFS in advanced stages, but not in early stages of GC.
CGB5 expression is common in gastric cancer patients, and its expression might independently predict poor overall survival and recurrence-free survival in advanced stages, but not in early stages of gastric cancer.
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Risk factors and survival outcomes in patients with breast cancer and lung metastasis: a population-based study
Abstract
The risk factors for morbidity and mortality in breast cancer lung metastases (BCLM) patients still remain poorly identified. The aim of this study was to assess the incidence and survival of BCLM and associated risk factors. Patients with BCLM were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate logistic regression analysis was used to determine the risk factors for BCLM. Predictors of factors associated with death were analyzed in Cox regression and Fine and Gray's test. Of the 11568 patients with stage IV breast cancer, 4213 (36.4%) had BCLM and 1214 (10.5%) had metastases confined to lungs. The median survival time for patients with BCLM was 21 months, and 15.5% of the patients were alive more than 3 years. The tumor subtype distribution was 45.3% HR−/HER2−, 12.2% HR+/HER2+, 7.8% HR−/HER2+, and 15.0% triple-negative subtype. Compared with patients without BCLM, those with BCLM were more likely to be aged, female, black, higher tumor grade, HR−/HER2+, HR+/HER2+, and triple-negative subtypes at diagnosis. Survival analysis showed that the aged, black race, HR−/HER2+, triple-negative subtype, higher grade were the independent risk factor for BCLM patients' survival, while HR+/HER2+ subtype, insured status, and married status suggested better prognosis. In conclusion, the incidence and prognosis of BCLM varied by tumor subtypes, age, and race. Elderly patients with HER2-positive or triple-negative tumors were more likely to have BCLM.
The aim of this study was to assess the incidence and survival in patients with breast cancer and lung metastases (BCLM) and associated risk factors on a population level. Of the 11,568 patients with stage IV breast cancer, 4213 (36.42%) had BCLM and 1214 (10.49%) had BCLM confined to lungs. Survival analysis showed that the aged, black race, HR−/HER2+, triple-negative subtype, higher grade were the independent risk factor for BCLM patients' survival, while HR+/HER2+ subtype, insured status, and married status suggested better prognosis.
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Prediction of radiotherapy response with a 5-microRNA signature-based nomogram in head and neck squamous cell carcinoma
Abstract
Radiotherapy is unlikely to benefit all patients with head and neck squamous cell carcinoma (HNSCC). Therefore, novel method is warranted to predict the radiotherapy response. Our study aimed to construct a microRNA (miRNA)-based nomogram to predict clinical outcomes of patients with HNSCC receiving radiotherapy. We screened out 56 differential miRNAs by analyzing 44 paired tumor and adjacent normal samples miRNA expression profiles from The Cancer Genome Atlas (TCGA). A total of 307 patients with HNSCC receiving adjuvant radiotherapy were randomly divided into a training set (n = 154) and a validation set (n = 153). In the training set, we combined the differential miRNA profiles with clinical outcomes, and LASSO regression model was applied to establish a 5-miRNA signature. The prediction accuracy of the 5-miRNA signature was further validated. In addition, target genes of these miRNAs were predicted, and Gene Ontology (GO) analysis as well as KEGG pathway analysis was executed. A 5-miRNA signature including miR-99a, miR-31, miR-410, miR-424, and miR-495 was identified. With a cutoff value of 1.2201 from Youden's index, the training set was divided into high-risk and low-risk groups, and the 5-year overall survival was significantly different (30% vs. 73%, HR 3.65, CI 2.46–8.16; P < 0.0001). Furthermore, our 5-miRNA signature revealed that only low-risk group would benefit from radiotherapy. Then, a nomogram combining 5-miRNA signature with clinical variables to predict radiotherapy response was constructed. The analysis of 108 target genes of these miRNAs revealed some potential mechanisms in HNSCC radiotherapy response for future investigations. In conclusion, the 5-miRNA signature-based nomogram is useful in predicting radiotherapy response in HNSCC and might become a promising tool to optimize radiation strategies.
We used LASSO regression model to establish a 5-miRNA signature, which serve as a novel and reliable biomarker for prediction of clinical outcomes in patients with HNSCC receiving radiotherapy. What's more, we developed a nomogram integrating the 5-miRNA signature with clinical features of each patient with HNSCC, which could be further used in the evaluation of radiotherapy responses. In addition, target genes of these miRNAs were predicted, and Gene Ontology (GO) analysis as well as KEGG analysis was executed to reveal some potential mechanisms in HNSCC radiotherapy response for future investigations.
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Chromosomal abnormality variation detected by G-banding is associated with prognosis of diffuse large B-cell lymphoma treated by R-CHOP-based therapy
Abstract
Diffuse large B-cell lymphoma (DLBCL), which is the most prevalent disease subtype of non-Hodgkin lymphoma, is highly heterogeneous in terms of cytogenetic and molecular features. This study retrospectively investigated the clinical impact of G-banding-defined chromosomal abnormality on treatment outcomes of DLBCL in the era of rituximab-containing immunochemotherapy. Of 181 patients who were diagnosed with DLBCL and treated with R-CHOP or an R-CHOP-like regimen between January 2006 and April 2014, metaphase spreads were evaluable for G-banding in 120. In these 120 patients, 40 were found to harbor a single chromosomal aberration type; 63 showed chromosomal abnormality variations (CAVs), which are defined by the presence of different types of chromosomal abnormalities in G-banding, including 19 with two CAVs and 44 with ≥3 CAVs; and 17 had normal karyotypes. No specific chromosomal break point or numerical abnormality was associated with overall survival (OS) or progression-free survival (PFS), but the presence of ≥3 CAVs was significantly associated with inferior OS rates (hazard ratio (HR): 2.222, 95% confidence interval (CI): 1.056–4.677, P = 0.031) and tended to be associated with shorter PFS (HR: 1.796, 95% CI: 0.965–3.344, P = 0.061). In addition, ≥3 CAVs more frequently accumulated in high-risk patients, as defined by several conventional prognostic indices, such as the revised International Prognostic Index. In conclusion, our results suggest that the emergence of more CAVs, especially ≥3, based on chromosomal instability underlies the development of high-risk disease features and a poor prognosis in DLBCL.
The existence of more chromosomal abnormality variations associates with poor prognosis in diffuse large B-cell lymphoma, indicating the negative prognostic impact of karyotypic evolution.
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Treatment-related mortality in newly diagnosed pediatric cancer: a population-based analysis
Abstract
Using a previously developed reliable and valid treatment-related mortality (TRM) definition, our objective was to describe the proportion of children newly diagnosed with cancer experiencing TRM and to identify risk factors for TRM in a population-based cohort. We included children with cancer <19 years diagnosed and treated in Ontario who were diagnosed between 2003 and 2012. Children with cancer were identified using data in a provincial registry. Cumulative incidence of TRM was calculated where progressive disease death was considered a competing event. Among the 5179 children included, 179 had TRM, 478 died of progressive disease, and 4522 were still alive. At 5 years, the cumulative incidence of TRM among the entire cohort was 3.9% (95% confidence interval (CI) 3.3–4.5%). When compared to brain tumor patients, leukemia and lymphoma patients had a significantly higher risk of TRM (hazard ratio (HR) 2.5, 95% CI: 1.6–4.0; P < 0.0001). Infants were at significantly higher risk of TRM across diagnostic groups. Other factors associated with higher risks of TRM were metastatic disease (P < 0.0001), diagnosis prior to 1 January 2008 (P = 0.001), hematopoietic stem cell transplantation (HSCT) (P < 0.0001), and relapse (P < 0.0001). The 5-year cumulative incidence of TRM was 3.9% among newly diagnosed children with cancer. Infants were at higher risk of TRM across diagnostic groups. Other risk factors for TRM were leukemia or lymphoma, metastatic disease, earlier diagnosis year, HSCT, and relapse. Future work should further refine prognostic factors by specific cancer diagnosis to best understand when and how to intervene to improve outcomes.
Objective was to describe the proportion of children newly diagnosed with cancer experiencing treatment-related mortality (TRM) and to identify risk factors for TRM in a population-based cohort. When compared to brain tumor patients, leukemia and lymphoma patients had a significantly higher risk of TRM. Infants were at significantly higher risk of TRM across diagnostic groups.
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Establishment and characterization of in vivo orthotopic bioluminescent xenograft models from human osteosarcoma cell lines in Swiss nude and NSG mice
Abstract
Osteosarcoma is one of the most common primary bone tumors in childhood and adolescence. Metastases occurrence at diagnosis or during disease evolution is the main therapeutic challenge. New drug evaluation to improve patient survival requires the development of various preclinical models mimicking at best the complexity of the disease and its metastatic potential. We describe here the development and characteristics of two orthotopic bioluminescent (Luc/mKate2) cell-derived xenograft (CDX) models, Saos-2-B-Luc/mKate2-CDX and HOS-Luc/mKate2-CDX, in different immune (nude and NSG mouse strains) and bone (intratibial and paratibial with periosteum activation) contexts. IVIS SpectrumCT system allowed both longitudinal computed tomography (CT) and bioluminescence real-time follow-up of primary tumor growth and metastatic spread, which was confirmed by histology. The murine immune context influenced tumor engraftment, primary tumor growth, and metastatic spread to lungs, bone, and spleen (an unusual localization in humans). Engraftment in NSG mice was found superior to that found in nude mice and intratibial bone environment more favorable to engraftment compared to paratibial injection. The genetic background of the two CDX models also led to distinct primary tumor behavior observed on CT scan. Saos-2-B-Luc/mKate2-CDX showed osteocondensed, HOS-Luc/mKate2-CDX osteolytic morphology. Bioluminescence defined a faster growth of the primary tumor and metastases in Saos-2-B-Luc/mKate2-CDX than in HOS-Luc/mKate2-CDX. The early detection of primary tumor growth and metastatic spread by bioluminescence allows an improved exploration of osteosarcoma disease at tumor progression, and metastatic spread, as well as the evaluations of anticancer treatments. Our orthotopic models with metastatic spread bring complementary information to other types of existing osteosarcoma models.
New osteosarcoma preclinical models in an orthotropic bone setting with the possibility to follow in vivo both primary tumor growth and metastatic spread will further help testing and development of new drug in this disease which outcome has not improved since several decades.
http://ift.tt/2EJDqsN
LncRNA HOTAIR influences cell growth, migration, invasion, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer
Abstract
To study the regulatory effect of lncRNA HOTAIR/miR-20a-5p/HMGA2 axis on breast cancer (BC) cell growth, cell mobility, invasiveness, and apoptosis. The microarray data of lncRNAs and mRNAs with differential expression in BC tissues were analyzed in the Cancer Genome Atlas (TCGA) database. LncRNA HOX transcript antisense RNA (lncRNA HOTAIR) expression in BC was assessed by qRT-PCR. Cell viability was confirmed using MTT and colony formation assay. Cell apoptosis was analyzed by TdT-mediated dUTP nick-end labeling (TUNEL) assay. Cell mobility and invasiveness were testified by transwell assay. RNA pull-down and dual luciferase assay were used for analysis of the correlation between lncRNA HOTAIR and miR-20a-5p, as well as relationship of miR-20a-5p with high mobility group AT-hook 2 (HMGA2). Tumor xenograft study was applied to confirm the correlation of lncRNA HOTAIR/miR-20a-5p/HMGA2 axis on BC development in vivo. The expression levels of the lncRNA HOTAIR were upregulated in BC tissues and cells. Knockdown lncRNA HOTAIR inhibited cell propagation and metastasis and facilitated cell apoptosis. MiR-20a-5p was a target of lncRNA HOTAIR and had a negative correlation with lncRNA HOTAIR. MiR-20a-5p overexpression in BC suppressed cell growth, mobility, and invasiveness and facilitated apoptosis. HMGA2 was a target of miR-20a-5p, which significantly induced carcinogenesis of BC. BC cells progression was mediated by lncRNA HOTAIR via affecting miR-20a-5p/HMGA2 in vivo. LncRNA HOTAIR affected cell growth, metastasis, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer.
The expression levels of the lncRNA HOTAIR were upregulated in BC tissues and cells. Knockdown lncRNA HOTAIR inhibited cell propagation and metastasis and facilitated cell apoptosis. LncRNA HOTAIR affected cell growth, metastasis, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer.
http://ift.tt/2CED14O
Prognostic variables for temporal lobe injury after intensity modulated-radiotherapy of nasopharyngeal carcinoma
Abstract
To determine predictive factors for temporal lobe injury (TLI) in nasopharyngeal carcinoma patient (NPC) treated with intensity-modulated radiation therapy (IMRT). A total of 695 NPC cases treated with IMRT were retrospectively analyzed. TLI was diagnosed on MRI images. Volume-dose histograms for 870 evaluable temporal lobes were analyzed, and the predictive factors for the occurrence of TLI was evaluated. Receiver operating characteristic curve (ROC) and Logistic regression analysis was used to determine volume-dose parameters that predict temporal lobe injury (TLI). Univariate and multivariate analysis were used to analyze the predictive factors for TLI. The radiation dose-tolerance model of temporal lobe was calculated by logistic dose-response model. The median follow-up time was 73 months. A total of 8.5% patients were diagnosed with TLI. Among all the volume-dose parameters, logistic regression model showed D2cc (the dose Gray delivered to 2 cubic centimeter volume) was an only independent predictive factor. Multivariate analysis showed D2cc of temporal lobe, fraction size of prescription, T stage, and chemotherapy were the independent predictive factors for TLI. Logistic dose-response model has indicated the TD5/5 and TD50/5 of D2cc are 60.3 Gy and 76.9 Gy, respectively. D2cc of temporal lobe, fraction size of prescription, T stage, and chemotherapy were the possible independent predictive factors for TLI after IMRT of NPC. Biologic effective doses (TD5/5 and TD50/5) of D2cc are considered to prevent TLI.
A total of 695 NPC cases treated with IMRT were retrospectively analyzed with the radiation-induced temporal lobe injury on MRI images. D2cc of temporal lobe, fraction size of prescription, T stage, and chemotherapy were the possible independent predictive factors for TLI after IMRT of NPC. Biologic effective doses (TD5/5 and TD50/5) of D2cc are considered to prevent TLI.
http://ift.tt/2EJDitj
CGB5 expression is independently associated with poor overall survival and recurrence-free survival in patients with advanced gastric cancer
Abstract
The human CGB5 gene encodes chorionic gonadotropin (hCG)β 5, which is aberrantly expressed in trophoblastic neoplasm and in some non-trophoblastic neoplasms. Fucntional studies observed that it involved tumor initiation, growth, and metastatic outgrowth. In this study, using data from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD), we assessed the independent prognostic value of CGB5 expression in patients with primary gastric cancer (GC). Results showed that CGB5 expression was nearly not expressed in normal GC tissues. In comparison, its expression was detected in 214 of the 415 primary GC cases (51.6%) in TCGA-STAD and was associated with poor response to primary therapy and a higher risk of recurrence and death. In early stages, CGB5 expression was not a prognostic factor in terms of OS (HR: 1.448; 95% CI: 0.811–2.588, P = 0.211) or RFS (HR: 1.659; 95% CI: 0.778–3.540, P = 0.190). However, its expression was independently associated with unfavorable OS (HR: 1.719; 95% CI: 1.115–2.651, P = 0.014) and RFS (HR: 3.602; 95% CI: 1.708–7.598, P = 0.001) in advanced stages. Using deep sequencing data from TCGA-STAD, we found that CGB5 expression was not related to its genetic amplification or DNA methylation in GC. Based on these findings, we infer that CGB5 expression is common in GC patients and its expression might independently predict poor OS and RFS in advanced stages, but not in early stages of GC.
CGB5 expression is common in gastric cancer patients, and its expression might independently predict poor overall survival and recurrence-free survival in advanced stages, but not in early stages of gastric cancer.
http://ift.tt/2CCp7jP
Risk factors and survival outcomes in patients with breast cancer and lung metastasis: a population-based study
Abstract
The risk factors for morbidity and mortality in breast cancer lung metastases (BCLM) patients still remain poorly identified. The aim of this study was to assess the incidence and survival of BCLM and associated risk factors. Patients with BCLM were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate logistic regression analysis was used to determine the risk factors for BCLM. Predictors of factors associated with death were analyzed in Cox regression and Fine and Gray's test. Of the 11568 patients with stage IV breast cancer, 4213 (36.4%) had BCLM and 1214 (10.5%) had metastases confined to lungs. The median survival time for patients with BCLM was 21 months, and 15.5% of the patients were alive more than 3 years. The tumor subtype distribution was 45.3% HR−/HER2−, 12.2% HR+/HER2+, 7.8% HR−/HER2+, and 15.0% triple-negative subtype. Compared with patients without BCLM, those with BCLM were more likely to be aged, female, black, higher tumor grade, HR−/HER2+, HR+/HER2+, and triple-negative subtypes at diagnosis. Survival analysis showed that the aged, black race, HR−/HER2+, triple-negative subtype, higher grade were the independent risk factor for BCLM patients' survival, while HR+/HER2+ subtype, insured status, and married status suggested better prognosis. In conclusion, the incidence and prognosis of BCLM varied by tumor subtypes, age, and race. Elderly patients with HER2-positive or triple-negative tumors were more likely to have BCLM.
The aim of this study was to assess the incidence and survival in patients with breast cancer and lung metastases (BCLM) and associated risk factors on a population level. Of the 11,568 patients with stage IV breast cancer, 4213 (36.42%) had BCLM and 1214 (10.49%) had BCLM confined to lungs. Survival analysis showed that the aged, black race, HR−/HER2+, triple-negative subtype, higher grade were the independent risk factor for BCLM patients' survival, while HR+/HER2+ subtype, insured status, and married status suggested better prognosis.
http://ift.tt/2ELNvW3
Prediction of radiotherapy response with a 5-microRNA signature-based nomogram in head and neck squamous cell carcinoma
Abstract
Radiotherapy is unlikely to benefit all patients with head and neck squamous cell carcinoma (HNSCC). Therefore, novel method is warranted to predict the radiotherapy response. Our study aimed to construct a microRNA (miRNA)-based nomogram to predict clinical outcomes of patients with HNSCC receiving radiotherapy. We screened out 56 differential miRNAs by analyzing 44 paired tumor and adjacent normal samples miRNA expression profiles from The Cancer Genome Atlas (TCGA). A total of 307 patients with HNSCC receiving adjuvant radiotherapy were randomly divided into a training set (n = 154) and a validation set (n = 153). In the training set, we combined the differential miRNA profiles with clinical outcomes, and LASSO regression model was applied to establish a 5-miRNA signature. The prediction accuracy of the 5-miRNA signature was further validated. In addition, target genes of these miRNAs were predicted, and Gene Ontology (GO) analysis as well as KEGG pathway analysis was executed. A 5-miRNA signature including miR-99a, miR-31, miR-410, miR-424, and miR-495 was identified. With a cutoff value of 1.2201 from Youden's index, the training set was divided into high-risk and low-risk groups, and the 5-year overall survival was significantly different (30% vs. 73%, HR 3.65, CI 2.46–8.16; P < 0.0001). Furthermore, our 5-miRNA signature revealed that only low-risk group would benefit from radiotherapy. Then, a nomogram combining 5-miRNA signature with clinical variables to predict radiotherapy response was constructed. The analysis of 108 target genes of these miRNAs revealed some potential mechanisms in HNSCC radiotherapy response for future investigations. In conclusion, the 5-miRNA signature-based nomogram is useful in predicting radiotherapy response in HNSCC and might become a promising tool to optimize radiation strategies.
We used LASSO regression model to establish a 5-miRNA signature, which serve as a novel and reliable biomarker for prediction of clinical outcomes in patients with HNSCC receiving radiotherapy. What's more, we developed a nomogram integrating the 5-miRNA signature with clinical features of each patient with HNSCC, which could be further used in the evaluation of radiotherapy responses. In addition, target genes of these miRNAs were predicted, and Gene Ontology (GO) analysis as well as KEGG analysis was executed to reveal some potential mechanisms in HNSCC radiotherapy response for future investigations.
http://ift.tt/2CE9XKE
Chromosomal abnormality variation detected by G-banding is associated with prognosis of diffuse large B-cell lymphoma treated by R-CHOP-based therapy
Abstract
Diffuse large B-cell lymphoma (DLBCL), which is the most prevalent disease subtype of non-Hodgkin lymphoma, is highly heterogeneous in terms of cytogenetic and molecular features. This study retrospectively investigated the clinical impact of G-banding-defined chromosomal abnormality on treatment outcomes of DLBCL in the era of rituximab-containing immunochemotherapy. Of 181 patients who were diagnosed with DLBCL and treated with R-CHOP or an R-CHOP-like regimen between January 2006 and April 2014, metaphase spreads were evaluable for G-banding in 120. In these 120 patients, 40 were found to harbor a single chromosomal aberration type; 63 showed chromosomal abnormality variations (CAVs), which are defined by the presence of different types of chromosomal abnormalities in G-banding, including 19 with two CAVs and 44 with ≥3 CAVs; and 17 had normal karyotypes. No specific chromosomal break point or numerical abnormality was associated with overall survival (OS) or progression-free survival (PFS), but the presence of ≥3 CAVs was significantly associated with inferior OS rates (hazard ratio (HR): 2.222, 95% confidence interval (CI): 1.056–4.677, P = 0.031) and tended to be associated with shorter PFS (HR: 1.796, 95% CI: 0.965–3.344, P = 0.061). In addition, ≥3 CAVs more frequently accumulated in high-risk patients, as defined by several conventional prognostic indices, such as the revised International Prognostic Index. In conclusion, our results suggest that the emergence of more CAVs, especially ≥3, based on chromosomal instability underlies the development of high-risk disease features and a poor prognosis in DLBCL.
The existence of more chromosomal abnormality variations associates with poor prognosis in diffuse large B-cell lymphoma, indicating the negative prognostic impact of karyotypic evolution.
http://ift.tt/2ELNv8v
Treatment-related mortality in newly diagnosed pediatric cancer: a population-based analysis
Abstract
Using a previously developed reliable and valid treatment-related mortality (TRM) definition, our objective was to describe the proportion of children newly diagnosed with cancer experiencing TRM and to identify risk factors for TRM in a population-based cohort. We included children with cancer <19 years diagnosed and treated in Ontario who were diagnosed between 2003 and 2012. Children with cancer were identified using data in a provincial registry. Cumulative incidence of TRM was calculated where progressive disease death was considered a competing event. Among the 5179 children included, 179 had TRM, 478 died of progressive disease, and 4522 were still alive. At 5 years, the cumulative incidence of TRM among the entire cohort was 3.9% (95% confidence interval (CI) 3.3–4.5%). When compared to brain tumor patients, leukemia and lymphoma patients had a significantly higher risk of TRM (hazard ratio (HR) 2.5, 95% CI: 1.6–4.0; P < 0.0001). Infants were at significantly higher risk of TRM across diagnostic groups. Other factors associated with higher risks of TRM were metastatic disease (P < 0.0001), diagnosis prior to 1 January 2008 (P = 0.001), hematopoietic stem cell transplantation (HSCT) (P < 0.0001), and relapse (P < 0.0001). The 5-year cumulative incidence of TRM was 3.9% among newly diagnosed children with cancer. Infants were at higher risk of TRM across diagnostic groups. Other risk factors for TRM were leukemia or lymphoma, metastatic disease, earlier diagnosis year, HSCT, and relapse. Future work should further refine prognostic factors by specific cancer diagnosis to best understand when and how to intervene to improve outcomes.
Objective was to describe the proportion of children newly diagnosed with cancer experiencing treatment-related mortality (TRM) and to identify risk factors for TRM in a population-based cohort. When compared to brain tumor patients, leukemia and lymphoma patients had a significantly higher risk of TRM. Infants were at significantly higher risk of TRM across diagnostic groups.
http://ift.tt/2CCIVDJ
The Generalized Anxiety Disorder Screener (GAD-7) and the anxiety module of the Hospital and Depression Scale (HADS-A) as screening tools for generalized anxiety disorder among cancer patients
Abstract
Objective
Anxiety in cancer patients may represent a normal psychological reaction. To detect patients with pathological levels, appropriate screeners with established cut-offs are needed. Given that previous research is sparse, we investigated the diagnostic accuracy of two frequently used screening tools in detecting generalized anxiety disorder (GAD).
Methods
We used data of a multi-center study including 2141 cancer patients. Diagnostic accuracy was investigated for the Generalized Anxiety Disorder Screener (GAD-7) and the anxiety module of the Hospital Anxiety and Depression Scale (HADS-A). GAD, assessed with the Composite International Diagnostic Interview for Oncology, served as a reference standard. Overall accuracy was measured with the area under the receiver operating characteristics curve (AUC). The AUC of the two screeners were statistically compared. We also calculated accuracy measures for selected cut-offs.
Results
Diagnostic accuracy could be interpreted as adequate for both screeners, with an identical AUC of .81 (95 % CI: .79 – .82). Consequently, the two screeners did not differ in their performance (p = .86). The best balance between sensitivity and specificity was found for cut-offs ≥ 7 (GAD-7) and ≥ 8 (HADS-A). The officially recommended thresholds for the GAD-7 (≥ 10) and the HADS-A (≥11) showed low sensitivities of 55 % and 48 %, respectively.
Conclusions
The GAD-7 and HADS-A showed AUC of adequate diagnostic accuracy and hence are applicable for GAD screening in cancer patients. Nevertheless, the choice of optimal cut-offs should be carefully evaluated.
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Post-traumatic growth in head and neck cancer survivors: is it possible and what are the correlates?
Abstract
Objectives
Posttraumatic growth (PTG) is a possible positive consequence of a traumatic event, such as cancer. Head and neck cancer (HNC) may be particularly traumatic, given its adverse effects on functional, psychological and social wellbeing. We investigated: extent of PTG; factors associated with PTG; and associations between PTG and health-related quality-of-life (HRQoL) in HNC survivors.
Methods
HNC survivors (ICD10 C00-C14, C32), identified from the population-based National Cancer Registry Ireland, completed a postal survey. PTG was assessed using the Posttraumatic Growth Inventory (PTG-I) and HRQoL with FACT-G and FACT-HN. Associations between socio-economic characteristics, social support, and clinical variables and PTG were examined using multivariable linear regression. Total HRQoL scores were compared in those with none-low PTG vs moderate-high PTG.
Results
583 survivors participated (response rate=59%). The mean PTG score was 55.74 (95%CI 53.15-58.33); 60% had moderate-high PTG. Survivors scored highest in the PTG-I domain appreciation of life. In multivariable analysis, being female, being younger, having more social support and having cancer-related financial stress were significantly associated with more PTG. HRQoL was significantly higher in those with moderate-high than no-little PTG (p<0.01)
Conclusion
A notable proportion of HNC survivors report PTG but growth is, on average, lower than reported for other cancers. Nonetheless, higher PTG appears related to better HRQoL. Further research would be valuable to understand the pathways by which HNC may lead to PTG and inform development of strategies to support and encourage PTG in this survivor population.
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The Generalized Anxiety Disorder Screener (GAD-7) and the anxiety module of the Hospital and Depression Scale (HADS-A) as screening tools for generalized anxiety disorder among cancer patients
Abstract
Objective
Anxiety in cancer patients may represent a normal psychological reaction. To detect patients with pathological levels, appropriate screeners with established cut-offs are needed. Given that previous research is sparse, we investigated the diagnostic accuracy of two frequently used screening tools in detecting generalized anxiety disorder (GAD).
Methods
We used data of a multi-center study including 2141 cancer patients. Diagnostic accuracy was investigated for the Generalized Anxiety Disorder Screener (GAD-7) and the anxiety module of the Hospital Anxiety and Depression Scale (HADS-A). GAD, assessed with the Composite International Diagnostic Interview for Oncology, served as a reference standard. Overall accuracy was measured with the area under the receiver operating characteristics curve (AUC). The AUC of the two screeners were statistically compared. We also calculated accuracy measures for selected cut-offs.
Results
Diagnostic accuracy could be interpreted as adequate for both screeners, with an identical AUC of .81 (95 % CI: .79 – .82). Consequently, the two screeners did not differ in their performance (p = .86). The best balance between sensitivity and specificity was found for cut-offs ≥ 7 (GAD-7) and ≥ 8 (HADS-A). The officially recommended thresholds for the GAD-7 (≥ 10) and the HADS-A (≥11) showed low sensitivities of 55 % and 48 %, respectively.
Conclusions
The GAD-7 and HADS-A showed AUC of adequate diagnostic accuracy and hence are applicable for GAD screening in cancer patients. Nevertheless, the choice of optimal cut-offs should be carefully evaluated.
http://ift.tt/2FopJfT
Post-traumatic growth in head and neck cancer survivors: is it possible and what are the correlates?
Abstract
Objectives
Posttraumatic growth (PTG) is a possible positive consequence of a traumatic event, such as cancer. Head and neck cancer (HNC) may be particularly traumatic, given its adverse effects on functional, psychological and social wellbeing. We investigated: extent of PTG; factors associated with PTG; and associations between PTG and health-related quality-of-life (HRQoL) in HNC survivors.
Methods
HNC survivors (ICD10 C00-C14, C32), identified from the population-based National Cancer Registry Ireland, completed a postal survey. PTG was assessed using the Posttraumatic Growth Inventory (PTG-I) and HRQoL with FACT-G and FACT-HN. Associations between socio-economic characteristics, social support, and clinical variables and PTG were examined using multivariable linear regression. Total HRQoL scores were compared in those with none-low PTG vs moderate-high PTG.
Results
583 survivors participated (response rate=59%). The mean PTG score was 55.74 (95%CI 53.15-58.33); 60% had moderate-high PTG. Survivors scored highest in the PTG-I domain appreciation of life. In multivariable analysis, being female, being younger, having more social support and having cancer-related financial stress were significantly associated with more PTG. HRQoL was significantly higher in those with moderate-high than no-little PTG (p<0.01)
Conclusion
A notable proportion of HNC survivors report PTG but growth is, on average, lower than reported for other cancers. Nonetheless, higher PTG appears related to better HRQoL. Further research would be valuable to understand the pathways by which HNC may lead to PTG and inform development of strategies to support and encourage PTG in this survivor population.
http://ift.tt/2EL7PH8
Central nervous system relapse in patients over 80 years with diffuse large B-cell lymphoma: an analysis of two LYSA studies
Abstract
CNS relapse is reported in 2–5% of diffuse large B-cell lymphoma (DLBCL) patients, dramatically decreasing overall survival (OS). Very few studies address incidence and risk factors of CNS relapse in very elderly patients, a challenging population to treat given their commonly associated comorbidities. A retrospective analysis was performed of 270 DLBCL patients >80 years treated between 2004 and 2013 in two multicentre phase II LYSA trials (LNH03-7B, LNH09-7B) evaluating the addition of rituximab or ofatumumab to mini-CHOP as front-line therapy. No patients received CNS prophylaxis. CNS relapse was evaluated according to cumulative incidence, patient characteristics, risk factors, and survival. Median age was 83 years (range: 79–95). After a median follow-up of 28.7 months, eight patients had CNS relapse (3.0%). Median time between inclusion and CNS relapse was 19.2 months (range: 3.2–32.6). Patients survived a median of 1.5 months after CNS relapse (range: 0.4–4.1). Median OS from relapse was significantly lower in CNS relapse patients (1.5 months, 95% CI: 0.4–3.5) compared to patients with non-CNS relapse (6.6 months; 95% CI: 4.6–11.9). No baseline characteristics were associated with CNS relapse. The proportion of patients with CNS disease did not differ significantly between patients with low-intermediate risk according to CNS-IPI and patients with high risk (3% vs. 2.8%, P = 1.00). CNS relapse cumulative incidence in very elderly treatment-naive patients is 1.8% at 2 years and is associated with poor survival. This population had a long median time to CNS relapse. Absence of prophylaxis did not strongly impact CNS relapse incidence.
Cumulative incidence of CNS relapse at 2 years in patients with diffuse large B-cell lymphoma aged over than 80 is 1.8% and is associated with a very poor survival. The absence of prophylaxis did not appear to have a strong impact on CNS relapse incidence. Consequently CNS prophylaxis can be avoided in this population given the potential for a negative impact of the associated toxicities.
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Employment benefits and job retention: evidence among patients with colorectal cancer
Abstract
A "health shock," that is, a large, unanticipated adverse health event, can have long-term financial implications for patients and their families. Colorectal cancer is the third most commonly diagnosed cancer among men and women and is an example of a specific health shock. We examined whether specific benefits (employer-based health insurance, paid sick leave, extended sick leave, unpaid time off, disability benefits) are associated with job retention after diagnosis and treatment of colorectal cancer. In 2011–14, we surveyed patients with Stage III colorectal cancer from two representative SEER registries. The final sample was 1301 patients (68% survey response rate). For this study, we excluded 735 respondents who were not employed and 20 with unknown employment status. The final analytic sample included 546 respondents. Job retention in the year following diagnosis was assessed, and multivariable logistic regression was used to evaluate associations between job retention and access to specific employment benefits. Employer-based health insurance (OR = 2.97; 95% CI = 1.56–6.01; P = 0.003) and paid sick leave (OR = 2.93; 95% CI = 1.23–6.98; P = 0.015) were significantly associated with job retention, after adjusting for sociodemographic, clinical, geographic, and job characteristics.
A "health shock," that is, a large, unanticipated adverse health event, can have long-term financial implications for patients and their families. We examined whether specific benefits (employer-based health insurance, paid sick leave, extended sick leave, unpaid time off, disability benefits) are associated with job retention after diagnosis and treatment of colorectal cancer, an example of a specific health shock. Employer-based health insurance and paid sick leave were associated with job retention.
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Central nervous system relapse in patients over 80 years with diffuse large B-cell lymphoma: an analysis of two LYSA studies
Abstract
CNS relapse is reported in 2–5% of diffuse large B-cell lymphoma (DLBCL) patients, dramatically decreasing overall survival (OS). Very few studies address incidence and risk factors of CNS relapse in very elderly patients, a challenging population to treat given their commonly associated comorbidities. A retrospective analysis was performed of 270 DLBCL patients >80 years treated between 2004 and 2013 in two multicentre phase II LYSA trials (LNH03-7B, LNH09-7B) evaluating the addition of rituximab or ofatumumab to mini-CHOP as front-line therapy. No patients received CNS prophylaxis. CNS relapse was evaluated according to cumulative incidence, patient characteristics, risk factors, and survival. Median age was 83 years (range: 79–95). After a median follow-up of 28.7 months, eight patients had CNS relapse (3.0%). Median time between inclusion and CNS relapse was 19.2 months (range: 3.2–32.6). Patients survived a median of 1.5 months after CNS relapse (range: 0.4–4.1). Median OS from relapse was significantly lower in CNS relapse patients (1.5 months, 95% CI: 0.4–3.5) compared to patients with non-CNS relapse (6.6 months; 95% CI: 4.6–11.9). No baseline characteristics were associated with CNS relapse. The proportion of patients with CNS disease did not differ significantly between patients with low-intermediate risk according to CNS-IPI and patients with high risk (3% vs. 2.8%, P = 1.00). CNS relapse cumulative incidence in very elderly treatment-naive patients is 1.8% at 2 years and is associated with poor survival. This population had a long median time to CNS relapse. Absence of prophylaxis did not strongly impact CNS relapse incidence.
Cumulative incidence of CNS relapse at 2 years in patients with diffuse large B-cell lymphoma aged over than 80 is 1.8% and is associated with a very poor survival. The absence of prophylaxis did not appear to have a strong impact on CNS relapse incidence. Consequently CNS prophylaxis can be avoided in this population given the potential for a negative impact of the associated toxicities.
http://ift.tt/2CeaOWK
Employment benefits and job retention: evidence among patients with colorectal cancer
Abstract
A "health shock," that is, a large, unanticipated adverse health event, can have long-term financial implications for patients and their families. Colorectal cancer is the third most commonly diagnosed cancer among men and women and is an example of a specific health shock. We examined whether specific benefits (employer-based health insurance, paid sick leave, extended sick leave, unpaid time off, disability benefits) are associated with job retention after diagnosis and treatment of colorectal cancer. In 2011–14, we surveyed patients with Stage III colorectal cancer from two representative SEER registries. The final sample was 1301 patients (68% survey response rate). For this study, we excluded 735 respondents who were not employed and 20 with unknown employment status. The final analytic sample included 546 respondents. Job retention in the year following diagnosis was assessed, and multivariable logistic regression was used to evaluate associations between job retention and access to specific employment benefits. Employer-based health insurance (OR = 2.97; 95% CI = 1.56–6.01; P = 0.003) and paid sick leave (OR = 2.93; 95% CI = 1.23–6.98; P = 0.015) were significantly associated with job retention, after adjusting for sociodemographic, clinical, geographic, and job characteristics.
A "health shock," that is, a large, unanticipated adverse health event, can have long-term financial implications for patients and their families. We examined whether specific benefits (employer-based health insurance, paid sick leave, extended sick leave, unpaid time off, disability benefits) are associated with job retention after diagnosis and treatment of colorectal cancer, an example of a specific health shock. Employer-based health insurance and paid sick leave were associated with job retention.
http://ift.tt/2otu7C7
Macrophage-Derived Extracellular Succinate Licenses Neural Stem Cells to Suppress Chronic Neuroinflammation
Publication date: Available online 22 February 2018
Source:Cell Stem Cell
Author(s): Luca Peruzzotti-Jametti, Joshua D. Bernstock, Nunzio Vicario, Ana S.H. Costa, Chee Keong Kwok, Tommaso Leonardi, Lee M. Booty, Iacopo Bicci, Beatrice Balzarotti, Giulio Volpe, Giulia Mallucci, Giulia Manferrari, Matteo Donegà, Nunzio Iraci, Alice Braga, John M. Hallenbeck, Michael P. Murphy, Frank Edenhofer, Christian Frezza, Stefano Pluchino
Neural stem cell (NSC) transplantation can influence immune responses and suppress inflammation in the CNS. Metabolites, such as succinate, modulate the phenotype and function of immune cells, but whether and how NSCs are also activated by such immunometabolites to control immunoreactivity and inflammatory responses is unclear. Here, we show that transplanted somatic and directly induced NSCs ameliorate chronic CNS inflammation by reducing succinate levels in the cerebrospinal fluid, thereby decreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage. Inflammatory MPs release succinate, which activates succinate receptor 1 (SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavenge extracellular succinate with consequential anti-inflammatory effects. Thus, our work reveals an unexpected role for the succinate-SUCNR1 axis in somatic and directly induced NSCs, which controls the response of stem cells to inflammatory metabolic signals released by type 1 MPs in the chronically inflamed brain.
Graphical abstract
Teaser
Peruzzotti-Jametti et al. demonstrate that somatic and directly induced brain stem cells injected into the cerebrospinal fluid of mice with experimental multiple sclerosis ameliorate chronic neuroinflammation. Grafted stem cells use SUCNR1 to decrease the inflammatory metabolite succinate, thus inducing a metabolic switch in endogenous macrophages and microglia toward an anti-inflammatory phenotype.http://ift.tt/2CeZdXE
Adult Wilms tumor with inferior vena cava thrombus and distal deep vein thrombosis – a case report and literature review
Abstract
Background
Adult Wilms tumor (WT, nephroblastoma) is a rare, but well-described renal neoplasm. Although inferior vena cava tumor thrombosis is present in up to 10% of Wilms tumors in childhood, only few cases of this clinical manifestation in adults have been reported. To the best of our knowledge, this is the first case of adult WT infiltrating into inferior vena cava (IVC) with concomitant distal deep vein thrombosis.
Case presentation
A 28-year-old male patient with gross hematuria and right flank pain was diagnosed with right kidney tumor penetrating to IVC. Preoperatively, acute distal thrombosis in inferior vena cava and lower extremities veins occurred. Right radical nephrectomy with tumor thrombectomy via cavotomy was performed. In order to prevent pulmonary embolism, IVC was ligated below left renal vein level. Histopathological examination revealed a triphasic nephroblastoma without anaplastic features. Postoperatively, patient was diagnosed with metastatic liver disease, which was treated with two lines of chemotherapy followed by radiotherapy with achievement of complete response.
Conclusions
Adult WT occurs usually in young patients, under 40 years of age. Neoadjuvant chemotherapy proved to be effective in children, resulting with tumor shrinkage and venous tumor thrombus regression. Therefore, percutaneous biopsy should be always considered in young patients presenting with renal tumor invading venous system. IVC ligation is a safe treatment option in the event of complete inferior vena cava occlusion due to distal thrombosis concomitant to tumor thrombus, provided collateral venous pathways are well-developed.
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Prediction of suboptimal cytoreductive surgery in patients with advanced ovarian cancer based on preoperative and intraoperative determination of the peritoneal carcinomatosis index
Abstract
Background
The peritoneal carcinomatosis index (PCI) can be used to quantify the tumor burden in patients with advanced ovarian cancer. The aim of the present study was to establish a predictive model for suboptimal cytoreductive surgery (SCS) (residual tumor of > 1 cm) using preoperative and intraoperative determination of the PCI.
Methods
In total, 110 consecutive patients treated for advanced ovarian cancer during a 4-year period in our institution were assessed. Eighty of these patients were eligible for primary debulking surgery and thus included in the present study. All data were prospectively collected and retrospectively evaluated. We determined the PCI both preoperatively and intraoperatively and assessed postoperative complications.
Results
A PCI of > 20 was the best cut-off with which to predict a risk of SCS among all three diagnostic techniques assessed in this study (computed tomography, laparoscopy, and laparotomy). Intraoperative PCI determination was associated with the lowest risk of false negatives for SCS when detecting a PCI of < 20. The combination of preoperative computed tomography and laparoscopy, when both techniques predicted SCS, was associated with the lowest risk of false positives for SCS when detecting a PCI of > 20.
Conclusion
The combination of computed tomography and laparoscopy to obtain the PCI can help to determine which patients with advanced ovarian cancer are suitable for primary debulking surgery and which should undergo neoadjuvant chemotherapy.
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The extremity localized classic osteosarcomas have better survival than the axial non-classics
Abstract
Background
Osteosarcoma is one of the most malignant primary bone cancers, while is rarely reported in China. Of note, very few data of prognosis has been documented in this region. Thus, we carried a retrospective study to identify prognostic factors and to analyze outcomes in patients of both classic and non-classic high-grade osteosarcomas. Classic osteosarcoma is defined as of high-grade histology, age below 40 years, with extremity localized primary tumor, and without detectable metastasis at primary diagnosis.
Methods
A total of 98 patients (68 classic and 30 non-classic) aged from 4 to 64 years old were diagnosed as high-grade osteosarcoma from 2008 to 2015 in Nanfang Hospital, Guangzhou, China. Univariate and multivariate analyses were performed to identify the independent predictors for overall survival and event-free survival. Kaplan-Meier method was used for survival analysis.
Results
The median overall survival was 117 vs. 21 months, and the median event-free survival was 31 vs. 6 months in classic and non-classic osteosarcoma, respectively. The most frequently found tumor site was around the knee. The classic osteosarcoma had better overall survival and event-free survival than the non-classics. Tumor site and primary metastasis were found to be associated with overall survival and event-free survival in the univariate analysis. In the multivariate Cox regression analysis, tumor site and primary metastasis were each verified as independent prognostic factors. However, no similar result was found in elevated serum alkaline phosphatase or lactate dehydrogenase. Amputation or limb salvage surgery had no significant effect on overall survival and event-free survival in the extremity osteosarcomas. Classic osteosarcomas with extremity tumor site and free of primary metastasis exhibited better overall survival and event-free survival, while the axial and metastatic non-classics exhibited the worse.
Conclusions
The extremity classic osteosarcomas have better survivals than the axial non-classic cases. Amputation and limb salvage surgery make no significant change in overall survival and event-free survival in the extremity osteosarcomas.
Trial registration
Nanfang2013071; Date of registration: 7 September 2013 (retrospectively registered).
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Adult Wilms tumor with inferior vena cava thrombus and distal deep vein thrombosis – a case report and literature review
Abstract
Background
Adult Wilms tumor (WT, nephroblastoma) is a rare, but well-described renal neoplasm. Although inferior vena cava tumor thrombosis is present in up to 10% of Wilms tumors in childhood, only few cases of this clinical manifestation in adults have been reported. To the best of our knowledge, this is the first case of adult WT infiltrating into inferior vena cava (IVC) with concomitant distal deep vein thrombosis.
Case presentation
A 28-year-old male patient with gross hematuria and right flank pain was diagnosed with right kidney tumor penetrating to IVC. Preoperatively, acute distal thrombosis in inferior vena cava and lower extremities veins occurred. Right radical nephrectomy with tumor thrombectomy via cavotomy was performed. In order to prevent pulmonary embolism, IVC was ligated below left renal vein level. Histopathological examination revealed a triphasic nephroblastoma without anaplastic features. Postoperatively, patient was diagnosed with metastatic liver disease, which was treated with two lines of chemotherapy followed by radiotherapy with achievement of complete response.
Conclusions
Adult WT occurs usually in young patients, under 40 years of age. Neoadjuvant chemotherapy proved to be effective in children, resulting with tumor shrinkage and venous tumor thrombus regression. Therefore, percutaneous biopsy should be always considered in young patients presenting with renal tumor invading venous system. IVC ligation is a safe treatment option in the event of complete inferior vena cava occlusion due to distal thrombosis concomitant to tumor thrombus, provided collateral venous pathways are well-developed.
http://ift.tt/2EVHFAT
Prediction of suboptimal cytoreductive surgery in patients with advanced ovarian cancer based on preoperative and intraoperative determination of the peritoneal carcinomatosis index
Abstract
Background
The peritoneal carcinomatosis index (PCI) can be used to quantify the tumor burden in patients with advanced ovarian cancer. The aim of the present study was to establish a predictive model for suboptimal cytoreductive surgery (SCS) (residual tumor of > 1 cm) using preoperative and intraoperative determination of the PCI.
Methods
In total, 110 consecutive patients treated for advanced ovarian cancer during a 4-year period in our institution were assessed. Eighty of these patients were eligible for primary debulking surgery and thus included in the present study. All data were prospectively collected and retrospectively evaluated. We determined the PCI both preoperatively and intraoperatively and assessed postoperative complications.
Results
A PCI of > 20 was the best cut-off with which to predict a risk of SCS among all three diagnostic techniques assessed in this study (computed tomography, laparoscopy, and laparotomy). Intraoperative PCI determination was associated with the lowest risk of false negatives for SCS when detecting a PCI of < 20. The combination of preoperative computed tomography and laparoscopy, when both techniques predicted SCS, was associated with the lowest risk of false positives for SCS when detecting a PCI of > 20.
Conclusion
The combination of computed tomography and laparoscopy to obtain the PCI can help to determine which patients with advanced ovarian cancer are suitable for primary debulking surgery and which should undergo neoadjuvant chemotherapy.
http://ift.tt/2sNi0VT
The extremity localized classic osteosarcomas have better survival than the axial non-classics
Abstract
Background
Osteosarcoma is one of the most malignant primary bone cancers, while is rarely reported in China. Of note, very few data of prognosis has been documented in this region. Thus, we carried a retrospective study to identify prognostic factors and to analyze outcomes in patients of both classic and non-classic high-grade osteosarcomas. Classic osteosarcoma is defined as of high-grade histology, age below 40 years, with extremity localized primary tumor, and without detectable metastasis at primary diagnosis.
Methods
A total of 98 patients (68 classic and 30 non-classic) aged from 4 to 64 years old were diagnosed as high-grade osteosarcoma from 2008 to 2015 in Nanfang Hospital, Guangzhou, China. Univariate and multivariate analyses were performed to identify the independent predictors for overall survival and event-free survival. Kaplan-Meier method was used for survival analysis.
Results
The median overall survival was 117 vs. 21 months, and the median event-free survival was 31 vs. 6 months in classic and non-classic osteosarcoma, respectively. The most frequently found tumor site was around the knee. The classic osteosarcoma had better overall survival and event-free survival than the non-classics. Tumor site and primary metastasis were found to be associated with overall survival and event-free survival in the univariate analysis. In the multivariate Cox regression analysis, tumor site and primary metastasis were each verified as independent prognostic factors. However, no similar result was found in elevated serum alkaline phosphatase or lactate dehydrogenase. Amputation or limb salvage surgery had no significant effect on overall survival and event-free survival in the extremity osteosarcomas. Classic osteosarcomas with extremity tumor site and free of primary metastasis exhibited better overall survival and event-free survival, while the axial and metastatic non-classics exhibited the worse.
Conclusions
The extremity classic osteosarcomas have better survivals than the axial non-classic cases. Amputation and limb salvage surgery make no significant change in overall survival and event-free survival in the extremity osteosarcomas.
Trial registration
Nanfang2013071; Date of registration: 7 September 2013 (retrospectively registered).
http://ift.tt/2EWh1I3
Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS
Publication date: Available online 22 February 2018
Source:Cancer Cell
Author(s): Takuji Yamauchi, Takeshi Masuda, Matthew C. Canver, Michael Seiler, Yuichiro Semba, Mohammad Shboul, Mohammed Al-Raqad, Manami Maeda, Vivien A.C. Schoonenberg, Mitchel A. Cole, Claudio Macias-Trevino, Yuichi Ishikawa, Qiuming Yao, Michitaka Nakano, Fumio Arai, Stuart H. Orkin, Bruno Reversade, Silvia Buonamici, Luca Pinello, Koichi Akashi, Daniel E. Bauer, Takahiro Maeda
To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy.
Graphical abstract
Teaser
Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.from Cancer via ola Kala on Inoreader http://ift.tt/2GDNXlw
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Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS
Publication date: Available online 22 February 2018
Source:Cancer Cell
Author(s): Takuji Yamauchi, Takeshi Masuda, Matthew C. Canver, Michael Seiler, Yuichiro Semba, Mohammad Shboul, Mohammed Al-Raqad, Manami Maeda, Vivien A.C. Schoonenberg, Mitchel A. Cole, Claudio Macias-Trevino, Yuichi Ishikawa, Qiuming Yao, Michitaka Nakano, Fumio Arai, Stuart H. Orkin, Bruno Reversade, Silvia Buonamici, Luca Pinello, Koichi Akashi, Daniel E. Bauer, Takahiro Maeda
To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy.
Graphical abstract
Teaser
Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.http://ift.tt/2GDNXlw
Ixazomib in the management of relapsed multiple myeloma
Future Oncology, Ahead of Print.
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Ixazomib in the management of relapsed multiple myeloma
Future Oncology, Ahead of Print.
http://ift.tt/2orVJHP
Reporting guidelines for oncology research: helping to maximise the impact of your research
Reporting guidelines for oncology research: helping to maximise the impact of your research
Reporting guidelines for oncology research: helping to maximise the impact of your research, Published online: 22 February 2018; doi:10.1038/bjc.2017.407
Reporting guidelines for oncology research: helping to maximise the impact of your research
http://ift.tt/2CEiLAu
EQUATOR-Oncology: reducing the latitude of cancer trial design and reporting
EQUATOR-Oncology: reducing the latitude of cancer trial design and reporting
EQUATOR-Oncology: reducing the latitude of cancer trial design and reporting, Published online: 22 February 2018; doi:10.1038/bjc.2017.427
EQUATOR-Oncology: reducing the latitude of cancer trial design and reporting
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Reporting guidelines for oncology research: helping to maximise the impact of your research
Reporting guidelines for oncology research: helping to maximise the impact of your research
Reporting guidelines for oncology research: helping to maximise the impact of your research, Published online: 22 February 2018; doi:10.1038/bjc.2017.407
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EQUATOR-Oncology: reducing the latitude of cancer trial design and reporting
EQUATOR-Oncology: reducing the latitude of cancer trial design and reporting
EQUATOR-Oncology: reducing the latitude of cancer trial design and reporting, Published online: 22 February 2018; doi:10.1038/bjc.2017.427
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Mass spectrometry-based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to PI3K inhibitors in triple negative breast cancers
Activation of phosphoinositide 3-kinase (PI3K) signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib in vitro. A complex in/del frameshift in PIK3CA decreased sensitivity to buparlisib via NEK9/MAP2K4-dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased omic analyses in uncovering resistance mechanisms to targeted therapy.
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Genetic Mosaicism and Cancer: Cause and Effect
Increasing theoretical and experimental evidence suggests that the genomes of both normal and cancer cells are subject to continuous changes as a result of copying errors during replication, defects in chromosome segregation during mitosis, and direct chemical attacks by reactive oxygen species. The process of cellular genetic diversification begins during embryonic development and continues throughout life, leading to the phenomenon of somatic mosaicism. New information about the genetic diversity of cells composing the body makes us reconsider the existing concepts of cancer etiology and pathogenesis. Here, I suggest that a progressively deteriorating microenvironment ("soil") generates the cancerous "seed" and favors its development. Cancer Res; 78(6); 1–4. ©2018 AACR.
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Can the Theory of Planned Behavior help explain attendance to follow-up care of childhood cancer survivors?
Abstract
Objective
Childhood cancer survivors are at high risk for late effects. Regular attendance to long-term follow-up care is recommended and helps monitoring survivors' health. Using the Theory of Planned Behavior (TPB) we aimed to 1) investigate the predictors of the intention to attend follow-up care, and 2) examine the associations between perceived control and behavioral intention with actual follow-up care attendance in Swiss childhood cancer survivors.
Methods
We conducted a questionnaire survey in Swiss childhood cancer survivors (diagnosed with cancer aged <16 years between 1990 and 2005; ≥5 years since diagnosis). We assessed TPB-related predictors (attitude, subjective norm, perceived control), intention to attend follow-up care, and actual attendance. We applied structural equation modeling to investigate predictors of intention, and logistic regression models to study the association between intention and actual attendance.
Results
Of 299 responders (166 (55.5%) females), 145 (48.5%) reported attending follow-up care. We found that subjective norm, i.e. survivors' perceived social pressure and support, (Coef.0.90, p<0.001) predicted the intention to attend follow-up; attitude and perceived control did not. Perceived control (OR=1.58, 95%CI:1.04–2.41) and intention to attend follow-up (OR=6.43, 95%CI:4.21-9.81) were positively associated with attendance.
Conclusions
To increase attendance, an effort should be made to sensitize partners, friends, parents and health care professionals on their important role in supporting survivors regarding follow-up care. Additionally, interventions promoting personal control over the follow-up attendance might further increase regular attendance.
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Managing unsolicited findings in genomics: a qualitative interview study with cancer patients.
Abstract
Objective
Next-generation sequencing (NGS) is increasingly being employed in the context of personalized cancer treatment. Anticipating unsolicited findings that may arise during a NGS procedure is a key consideration; however, little is known about cancer patients' intentions, needs, and preferences concerning the return of unsolicited findings.
Methods
A qualitative design using individual semi-structured interviews with 24 cancer patients was utilized to explore patients' decisions on whether to receive unsolicited findings from NGS. These interviews were subsequently analyzed using the constant comparative method to develop codes and themes.
Results
We identified four interrelated themes that emerged in the context of the return of unsolicited findings. First, we describe how cancer patients expressed a strong need to control their lives. Second, we show the importance of family dynamics. Third, the NGS procedure regarding unsolicited findings is perceived as cognitively complex, and fourth, the procedure is also considered emotionally complex.
Conclusions
The results of our study contribute to a better understanding of what cancer patients consider important and what may motivate and influence them when making decisions on the disclosure of unsolicited findings following NGS. We show how Joel Feinberg's classification of autonomy may help clinicians to better understand cancer patients' desire for autonomous decision making while also acknowledging the emotional and cognitive difficulties regarding the disclosure of unsolicited findings.These insights could be helpful for clinicians to guide patients through this complex process.
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Mass spectrometry-based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to PI3K inhibitors in triple negative breast cancers
Activation of phosphoinositide 3-kinase (PI3K) signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib in vitro. A complex in/del frameshift in PIK3CA decreased sensitivity to buparlisib via NEK9/MAP2K4-dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased omic analyses in uncovering resistance mechanisms to targeted therapy.
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Genetic Mosaicism and Cancer: Cause and Effect
Increasing theoretical and experimental evidence suggests that the genomes of both normal and cancer cells are subject to continuous changes as a result of copying errors during replication, defects in chromosome segregation during mitosis, and direct chemical attacks by reactive oxygen species. The process of cellular genetic diversification begins during embryonic development and continues throughout life, leading to the phenomenon of somatic mosaicism. New information about the genetic diversity of cells composing the body makes us reconsider the existing concepts of cancer etiology and pathogenesis. Here, I suggest that a progressively deteriorating microenvironment ("soil") generates the cancerous "seed" and favors its development. Cancer Res; 78(6); 1–4. ©2018 AACR.
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Can the Theory of Planned Behavior help explain attendance to follow-up care of childhood cancer survivors?
Abstract
Objective
Childhood cancer survivors are at high risk for late effects. Regular attendance to long-term follow-up care is recommended and helps monitoring survivors' health. Using the Theory of Planned Behavior (TPB) we aimed to 1) investigate the predictors of the intention to attend follow-up care, and 2) examine the associations between perceived control and behavioral intention with actual follow-up care attendance in Swiss childhood cancer survivors.
Methods
We conducted a questionnaire survey in Swiss childhood cancer survivors (diagnosed with cancer aged <16 years between 1990 and 2005; ≥5 years since diagnosis). We assessed TPB-related predictors (attitude, subjective norm, perceived control), intention to attend follow-up care, and actual attendance. We applied structural equation modeling to investigate predictors of intention, and logistic regression models to study the association between intention and actual attendance.
Results
Of 299 responders (166 (55.5%) females), 145 (48.5%) reported attending follow-up care. We found that subjective norm, i.e. survivors' perceived social pressure and support, (Coef.0.90, p<0.001) predicted the intention to attend follow-up; attitude and perceived control did not. Perceived control (OR=1.58, 95%CI:1.04–2.41) and intention to attend follow-up (OR=6.43, 95%CI:4.21-9.81) were positively associated with attendance.
Conclusions
To increase attendance, an effort should be made to sensitize partners, friends, parents and health care professionals on their important role in supporting survivors regarding follow-up care. Additionally, interventions promoting personal control over the follow-up attendance might further increase regular attendance.
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Managing unsolicited findings in genomics: a qualitative interview study with cancer patients.
Abstract
Objective
Next-generation sequencing (NGS) is increasingly being employed in the context of personalized cancer treatment. Anticipating unsolicited findings that may arise during a NGS procedure is a key consideration; however, little is known about cancer patients' intentions, needs, and preferences concerning the return of unsolicited findings.
Methods
A qualitative design using individual semi-structured interviews with 24 cancer patients was utilized to explore patients' decisions on whether to receive unsolicited findings from NGS. These interviews were subsequently analyzed using the constant comparative method to develop codes and themes.
Results
We identified four interrelated themes that emerged in the context of the return of unsolicited findings. First, we describe how cancer patients expressed a strong need to control their lives. Second, we show the importance of family dynamics. Third, the NGS procedure regarding unsolicited findings is perceived as cognitively complex, and fourth, the procedure is also considered emotionally complex.
Conclusions
The results of our study contribute to a better understanding of what cancer patients consider important and what may motivate and influence them when making decisions on the disclosure of unsolicited findings following NGS. We show how Joel Feinberg's classification of autonomy may help clinicians to better understand cancer patients' desire for autonomous decision making while also acknowledging the emotional and cognitive difficulties regarding the disclosure of unsolicited findings.These insights could be helpful for clinicians to guide patients through this complex process.
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Clinical Factors Predict Atezolizumab Response [News in Brief]
Six clinical factors predict survival of patients with bladder cancer after treatment with PD-L1 inhibitor.
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CAR T-cell Therapies Produce Durable Remissions [News in Brief]
Patients with acute lymphoblastic leukemia successfully treated with CAR T cells at cancer centers around the world.
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Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: the Susan G. Komen Tissue Bank
Abstract
Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 to 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay. Hematoxilyn & eosin-stained tissue sections were assessed for numbers of TDLUs ("TDLU count"). Zero-inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p=0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p<0.0001). Postmenopausal IGFBP-3 was inversely associated with TDLU count among AA (RRT3vs.T1=0.49, 95% CI=0.28-0.84, p-trend=0.04) and Caucasian (RRT3vs.T1=0.64, 95% CI=0.42-0.98, p-trend=0.04) women. In premenopausal women, higher IGF-I:IGFBP-3 ratios were associated with higher TDLU count in Caucasian (RRT3vs.T1=1.33, 95% CI=1.02-1.75, p-trend=0.04), but not in AA (RRT3vs.T1=0.65, 95% CI=0.42-1.00, p-trend=0.05), women. Our data suggest a role of the IGF system, particularly IGFBP-3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women. This article is protected by copyright. All rights reserved.
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Polyunsaturated fatty acids and risk of melanoma: A Mendelian randomisation analysis
Abstract
Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk - putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomised controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma.
To perform MR we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for example, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17th percentile to the median.
Raising PUFA levels by a large amount (increasing DPA by 0.17 units) only negligibly changed melanoma risk - Odds Ratio [OR] = 1.03 (95% Confidence Interval [CI] = 0.96 - 1.10). Other PUFAs yielded similar results as DPA. Our MR analysis suggests that the effect of PUFA levels on melanoma risk is either zero or very small. This article is protected by copyright. All rights reserved.
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Tumor-associated auto-antibodies as early detection markers for ovarian cancer? A prospective evaluation
Abstract
Immuno-proteomic screening has identified several tumor-associated auto-antibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies.
We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53, and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited. This article is protected by copyright. All rights reserved.
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