Future Oncology Ahead of Print.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 28 Απριλίου 2017
Proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in Asian patients with breast cancer: an exploratory comparison from two Phase III trials
Proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in Asian patients with breast cancer: an exploratory comparison from two Phase III trials
Future Oncology Ahead of Print.
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Proposed biosimilar pegfilgrastim (LA-EP2006) compared with reference pegfilgrastim in Asian patients with breast cancer: an exploratory comparison from two Phase III trials
Future Oncology Ahead of Print.
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Intravoxel incoherent motion DWI of the pancreatic adenocarcinomas: monoexponential and biexponential apparent diffusion parameters and histopathological correlations
Abstract
Background
To investigate the associations between the diffusion parameters obtained from multiple-b-values diffusion weighted imaging (DWI) of pancreatic ductal adenocarcinoma (PDAC) and the aggressiveness and local stage prediction, and assess the values of the quantitative parameters for the discrimination of tumors from healthy pancreas.
Methods
Fifty-one patients with surgical pathology-proven PDAC (size, 35 ± 12 mm) and fifty-seven healthy volunteers were enrolled. Diffusion parameters including monoexponential apparent diffusion coefficient (ADCb and ADCtotal) and biexponential intravoxel incoherent motion (IVIM) parameters (ADCslow, ADCfast and f) based on 9 b-values (0 to 1000s/mm2) DWI were calculated for the lesions and the healthy pancreas. These parameters were compared by grades of differentiation, lymph node status, tumor stage and location. The diagnostic performances were calculated and compared by using the receiver operating characteristic curves (ROC) analyses.
Results
There was no statistically significant difference in ADCb, ADCtotal, ADCslow, ADCfast or f between PDAC stage T1/T2 and stage T3/T4 or moderately differentiated versus poorly differentiated PDAC (p = 0.060-0.941). In addition, no significant differences were observed for the quantitative parameters between tumors located in the pancreatic head versus other pancreatic regions (p = 0.203-0.954) or between tumors with and without metastatic peri-pancreatic lymph nodes (p = 0.313-0.917). ADC25-600, ADC1000, ADCtotal and ADCfast were significantly lower for PDAC compared the healthy pancreas (all p < 0.05). ROC analyses showed the area under curve for ADC20 was the largest (0.911) to distinguish PDAC from normal pancreas (cut-off value, 5.58 × 10−3mm2/s) and had the highest combined sensitivity (89.5%) and specificity (82.4%).
Conclusions
Multiple-b-values DWI derived monoexponential and biexponential parameters of PDAC do not exhibit significance dependence on tumor grade or tumor characteristics. ADC20 provided the best accuracy for differentiating PDAC from healthy pancreas in the study.
http://ift.tt/2qfKzsz
Intravoxel incoherent motion DWI of the pancreatic adenocarcinomas: monoexponential and biexponential apparent diffusion parameters and histopathological correlations
Abstract
Background
To investigate the associations between the diffusion parameters obtained from multiple-b-values diffusion weighted imaging (DWI) of pancreatic ductal adenocarcinoma (PDAC) and the aggressiveness and local stage prediction, and assess the values of the quantitative parameters for the discrimination of tumors from healthy pancreas.
Methods
Fifty-one patients with surgical pathology-proven PDAC (size, 35 ± 12 mm) and fifty-seven healthy volunteers were enrolled. Diffusion parameters including monoexponential apparent diffusion coefficient (ADCb and ADCtotal) and biexponential intravoxel incoherent motion (IVIM) parameters (ADCslow, ADCfast and f) based on 9 b-values (0 to 1000s/mm2) DWI were calculated for the lesions and the healthy pancreas. These parameters were compared by grades of differentiation, lymph node status, tumor stage and location. The diagnostic performances were calculated and compared by using the receiver operating characteristic curves (ROC) analyses.
Results
There was no statistically significant difference in ADCb, ADCtotal, ADCslow, ADCfast or f between PDAC stage T1/T2 and stage T3/T4 or moderately differentiated versus poorly differentiated PDAC (p = 0.060-0.941). In addition, no significant differences were observed for the quantitative parameters between tumors located in the pancreatic head versus other pancreatic regions (p = 0.203-0.954) or between tumors with and without metastatic peri-pancreatic lymph nodes (p = 0.313-0.917). ADC25-600, ADC1000, ADCtotal and ADCfast were significantly lower for PDAC compared the healthy pancreas (all p < 0.05). ROC analyses showed the area under curve for ADC20 was the largest (0.911) to distinguish PDAC from normal pancreas (cut-off value, 5.58 × 10−3mm2/s) and had the highest combined sensitivity (89.5%) and specificity (82.4%).
Conclusions
Multiple-b-values DWI derived monoexponential and biexponential parameters of PDAC do not exhibit significance dependence on tumor grade or tumor characteristics. ADC20 provided the best accuracy for differentiating PDAC from healthy pancreas in the study.
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Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: A Japanese multicenter pancreatic NEN-G3 study
Purpose: <p>Patients with Pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathological and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.</p> Experimental Design: 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histological subtype (NET-G3 versus pancreatic neuroendocrine carcinoma (NEC-G3)) were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed. <br /><br />Results: <p>70 patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-LI (median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis were significantly different between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P<0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% versus normal Rb, 24%, p=0.006; mutated KRAS, 77% versus wild-type, 23%, p=0.023). Rb was a predictive marker for response to platinum-based chemotherapy even in NEC-G3 (P=0.035).</p> Conclusions: <p>NET-G3 and NEC-G3 showed distinct clinicopathological characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3.
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Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: A Japanese multicenter pancreatic NEN-G3 study
Purpose: <p>Patients with Pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathological and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.</p> Experimental Design: 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histological subtype (NET-G3 versus pancreatic neuroendocrine carcinoma (NEC-G3)) were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed. <br /><br />Results: <p>70 patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-LI (median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis were significantly different between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P<0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% versus normal Rb, 24%, p=0.006; mutated KRAS, 77% versus wild-type, 23%, p=0.023). Rb was a predictive marker for response to platinum-based chemotherapy even in NEC-G3 (P=0.035).</p> Conclusions: <p>NET-G3 and NEC-G3 showed distinct clinicopathological characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3.
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THERAPEUTIC RATIONALE TO TARGET HIGHLY EXPRESSED CDK7 CONFERRING POOR OUTCOMES IN TRIPLE-NEGATIVE BREAST CANCER
Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell cycle-related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n = 383) and the METABRIC TNBC dataset (n = 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n = 109) and the METABRIC TNBC cohort (n = 203). The highly specific CDK7 kinase inhibitors BS-181 and THZ1 each down-regulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.
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Widespread use of misidentified cell line KB (HeLa): Incorrect attribution and its impact revealed through mining the scientific literature
Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell line, KB (HeLa), on the scientific literature. We identified 574 articles between 2000 and 2014 that provided an incorrect attribution for KB, in accordance with its false identity as oral epidermoid carcinoma, but only 57 articles that provided a correct attribution for KB, as HeLa or cervical adenocarcinoma. Statistical analysis of 57 Correct and 171 Incorrect articles showed that the number of citations to these articles increased over time. Content analysis of 200 citing articles showed there was a tendency to describe the cell line in accordance with the description in the cited paper. Analysis of journal impact factor showed no significant difference between Correct and Incorrect groups. Articles using KB or citing that usage were most frequently published in the subject areas of pharmacology, pharmacy, oncology, and medicinal chemistry. These findings are important for science policy and support the need for journals to require authentication testing as a condition of publication.
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THERAPEUTIC RATIONALE TO TARGET HIGHLY EXPRESSED CDK7 CONFERRING POOR OUTCOMES IN TRIPLE-NEGATIVE BREAST CANCER
Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell cycle-related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n = 383) and the METABRIC TNBC dataset (n = 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n = 109) and the METABRIC TNBC cohort (n = 203). The highly specific CDK7 kinase inhibitors BS-181 and THZ1 each down-regulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.
http://ift.tt/2qoDAdw
CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer
Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as pre-metastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a pre-metastatic niche that ultimately promoted liver metastases. Importantly, pre-metastatic liver-infiltrating MDSC induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSC to form a pre-metastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to pre-metastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSC are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease.
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Widespread use of misidentified cell line KB (HeLa): Incorrect attribution and its impact revealed through mining the scientific literature
Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell line, KB (HeLa), on the scientific literature. We identified 574 articles between 2000 and 2014 that provided an incorrect attribution for KB, in accordance with its false identity as oral epidermoid carcinoma, but only 57 articles that provided a correct attribution for KB, as HeLa or cervical adenocarcinoma. Statistical analysis of 57 Correct and 171 Incorrect articles showed that the number of citations to these articles increased over time. Content analysis of 200 citing articles showed there was a tendency to describe the cell line in accordance with the description in the cited paper. Analysis of journal impact factor showed no significant difference between Correct and Incorrect groups. Articles using KB or citing that usage were most frequently published in the subject areas of pharmacology, pharmacy, oncology, and medicinal chemistry. These findings are important for science policy and support the need for journals to require authentication testing as a condition of publication.
http://ift.tt/2pHys83
CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer
Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as pre-metastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a pre-metastatic niche that ultimately promoted liver metastases. Importantly, pre-metastatic liver-infiltrating MDSC induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSC to form a pre-metastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to pre-metastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSC are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease.
http://ift.tt/2qoE1o6
Expenditure and financial burden for the diagnosis and treatment of colorectal cancer in China: a hospital-based, multicenter, cross-sectional survey
The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden and effect of CRC di...
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Expenditure and financial burden for the diagnosis and treatment of colorectal cancer in China: a hospital-based, multicenter, cross-sectional survey
The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden and effect of CRC di...
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Delivered dose can be a better predictor of rectal toxicity than planned dose in prostate radiotherapy
For the first time, delivered dose to the rectum has been calculated and accumulated throughout the course of prostate radiotherapy using megavoltage computed tomography (MVCT) image guidance scans. Dosimetric parameters were linked with toxicity to test the hypothesis that delivered dose is a stronger predictor of toxicity than planned dose.
http://ift.tt/2oRi4wT
Pulmonary function after lung tumor stereotactic ablative radiotherapy depends on regional ventilation within irradiated lung
To determine if regional ventilation within irradiated lung volume predicts change in pulmonary function test (PFT) measurements after stereotactic ablative radiotherapy (SABR) of lung tumors.
http://ift.tt/2punCkM
Does age really matter? Radiotherapy in elderly patients with glioblastoma, the Munich experience
Abstract
Background
Glioblastoma is usually diagnosed around the age of 60–70 years. Patients older than 65 years are frequently described as "elderly". Several trials with monotherapy have established treatment regimens that offer therapies with reduced side effects but reduced efficacy. We analysed the outcome of elderly glioblastoma patients treated at our facility.
Methods
We performed a retrospective analysis of 62 consecutive patients older than 65 years treated for a primary glioblastoma at our facility from 2009 to 2015.
Results
Median age was 69.6 years (range 65.1–85.6 years); median OS of the entire cohort was 10.9 months. ECOG, MGMT and extent of resection but not age and the time from surgery to radiotherapy were associated with longer survival. Patients treated with adjuvant chemotherapy had a significantly longer survival (20.5 vs. 7.8 months). Furthermore, salvage therapies were associated with significant improved survival when compared to Best Supportive Care (22.3 vs. 8.8 months).
Conclusion
Also elderly patients are likely to benefit from an aggressive treatment after primary diagnosis of glioblastoma.
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Dose tracking assessment for image-guided radiotherapy of the prostate bed and the impact on clinical workflow
Abstract
Background
The cumulative dose was compared with the planned dose among fourteen patients undergoing image-guided, intensity-modulated radiotherapy of the prostate bed. Moreover, we investigated the feasibility of adding dose tracking to the routine workflow for radiotherapy.
Methods
Daily cone beam computed tomography was conducted for image-guided radiotherapy, and weekly cumulative delivered doses were calculated for dose tracking. Deformable image registration was applied to map weekly dose distributions to the original treatment plan and to create a cumulative dose distribution. The dose–volume histogram (DVH) cut-off points for the rectum and bladder and the planning target volume (PTV), were used to compare the planned and cumulative delivered doses. The additional time required by the departmental staff to complete these duties was recorded.
Results
The PTV coverage of the delivered treatment did not satisfy the expected goal for three patients (V98% >98%). In another three patients, the DVH cut-off point for the bladder was higher than the limits, while for the rectum, treatment was as expected in all cases (two patients failed both their bladder constraints and the PTV coverage). Overall, four patients did not satisfy one or more criteria at the end of their treatment.
Conclusions
A well-defined strategy for dose tracking assessment is feasible, would have minimal impact on the workload of a radiotherapy department, and may offer objective information to support radiation oncologists in making decisions about adaptive procedures.
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Does age really matter? Radiotherapy in elderly patients with glioblastoma, the Munich experience
Abstract
Background
Glioblastoma is usually diagnosed around the age of 60–70 years. Patients older than 65 years are frequently described as "elderly". Several trials with monotherapy have established treatment regimens that offer therapies with reduced side effects but reduced efficacy. We analysed the outcome of elderly glioblastoma patients treated at our facility.
Methods
We performed a retrospective analysis of 62 consecutive patients older than 65 years treated for a primary glioblastoma at our facility from 2009 to 2015.
Results
Median age was 69.6 years (range 65.1–85.6 years); median OS of the entire cohort was 10.9 months. ECOG, MGMT and extent of resection but not age and the time from surgery to radiotherapy were associated with longer survival. Patients treated with adjuvant chemotherapy had a significantly longer survival (20.5 vs. 7.8 months). Furthermore, salvage therapies were associated with significant improved survival when compared to Best Supportive Care (22.3 vs. 8.8 months).
Conclusion
Also elderly patients are likely to benefit from an aggressive treatment after primary diagnosis of glioblastoma.
http://ift.tt/2oGD2Dg
Dose tracking assessment for image-guided radiotherapy of the prostate bed and the impact on clinical workflow
Abstract
Background
The cumulative dose was compared with the planned dose among fourteen patients undergoing image-guided, intensity-modulated radiotherapy of the prostate bed. Moreover, we investigated the feasibility of adding dose tracking to the routine workflow for radiotherapy.
Methods
Daily cone beam computed tomography was conducted for image-guided radiotherapy, and weekly cumulative delivered doses were calculated for dose tracking. Deformable image registration was applied to map weekly dose distributions to the original treatment plan and to create a cumulative dose distribution. The dose–volume histogram (DVH) cut-off points for the rectum and bladder and the planning target volume (PTV), were used to compare the planned and cumulative delivered doses. The additional time required by the departmental staff to complete these duties was recorded.
Results
The PTV coverage of the delivered treatment did not satisfy the expected goal for three patients (V98% >98%). In another three patients, the DVH cut-off point for the bladder was higher than the limits, while for the rectum, treatment was as expected in all cases (two patients failed both their bladder constraints and the PTV coverage). Overall, four patients did not satisfy one or more criteria at the end of their treatment.
Conclusions
A well-defined strategy for dose tracking assessment is feasible, would have minimal impact on the workload of a radiotherapy department, and may offer objective information to support radiation oncologists in making decisions about adaptive procedures.
http://ift.tt/2pqvJg1
Oxytocin inhibits head and neck squamous cell carcinoma cell migration by early growth response-1 upregulation.
The effect of oxytocin (OXT) on cancer invasion is controversial. Few studies have examined the effect of early growth response-1 (EGR1) on the invasion of head and neck squamous cell carcinoma (HNSCC). Here, we evaluated how EGR1 affects HNSCC cell migration through the molecular mechanism of OXT in exerting anti-invasion activity. Matrigel invasion and wound-healing assays were used to measure the in-vitro cell migration. The molecular mechanism of OXT was assessed by knockdown or overexpression of EGR1 in HNSCC cells. Three-dimensional (3-D) spheroids formation, followed by the image analysis for quantification was performed. OXT at 500 nmol/l increased mRNA and protein expression of E-cadherin without cytotoxicity. OXT upregulated mRNA and protein expression of EGR1 in 6 h. p53, phosphatase and tensin, and p21 expression was increased in an EGR1-dependent manner with OXT treatment. In addition, OXT significantly downregulated 3-D spheroids' formation according to spheroids' number and size. Our data showed that OXT downregulated HNSCC cell migration by EGR1 upregulation. OXT inhibited spheroids' formation of HNSCC cells under 3-D culture conditions. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Oxytocin inhibits head and neck squamous cell carcinoma cell migration by early growth response-1 upregulation.
The effect of oxytocin (OXT) on cancer invasion is controversial. Few studies have examined the effect of early growth response-1 (EGR1) on the invasion of head and neck squamous cell carcinoma (HNSCC). Here, we evaluated how EGR1 affects HNSCC cell migration through the molecular mechanism of OXT in exerting anti-invasion activity. Matrigel invasion and wound-healing assays were used to measure the in-vitro cell migration. The molecular mechanism of OXT was assessed by knockdown or overexpression of EGR1 in HNSCC cells. Three-dimensional (3-D) spheroids formation, followed by the image analysis for quantification was performed. OXT at 500 nmol/l increased mRNA and protein expression of E-cadherin without cytotoxicity. OXT upregulated mRNA and protein expression of EGR1 in 6 h. p53, phosphatase and tensin, and p21 expression was increased in an EGR1-dependent manner with OXT treatment. In addition, OXT significantly downregulated 3-D spheroids' formation according to spheroids' number and size. Our data showed that OXT downregulated HNSCC cell migration by EGR1 upregulation. OXT inhibited spheroids' formation of HNSCC cells under 3-D culture conditions. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Carotid atherosclerotic plaques standardised uptake values: software challenges and reproducibility
Abstract
Background
Positron emission tomography–computed tomography (PET-CT) carotid standardised uptake values (SUV) of 18F-fluorodeoxyglucose (18FDG) have been proposed as an inflammatory biomarker for determining cerebrovascular diseases such as stroke. Consideration of varying methodological approaches and software packages is critical to the calculation of accurate SUVs in cross-sectional and longitudinal patient studies. The aim of this study was to investigate whether or not carotid atherosclerotic plaque SUVs are consistent and reproducible between software packages.
18FDG-PET SUVs of carotids were taken in 101 patients using two different software packages. Quality assurance checks were performed to standardise techniques before commencing the analysis where data from five to seven anatomical sites were measured. A total of ten regions of interest were drawn on each site analysed. Statistical analyses were then performed to compare SUV measurements from the two software packages and to explore reproducibility of measurements. Lastly, the time taken to complete each analysis was measured and compared.
Results
Statistically significant differences in SUV measurements, between the two software packages, ranging from 9 to 21.8% were found depending on ROI location. In 79% (n = 23) of the ROI locations, the differences between the SUV measurements from each software package were found to be statistically significant. The time taken to perform the analyses and export data from the software packages also varied considerably.
Conclusions
This study highlights the importance of standardising all aspects of methodological approaches to ensure accuracy and reproducibility. Physicians must be aware that when a PET-CT data set is analysed, subsequent follow-ups must be verified, if possible, with the same software package or cross-calibration between packages should be performed.
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Carotid atherosclerotic plaques standardised uptake values: software challenges and reproducibility
Abstract
Background
Positron emission tomography–computed tomography (PET-CT) carotid standardised uptake values (SUV) of 18F-fluorodeoxyglucose (18FDG) have been proposed as an inflammatory biomarker for determining cerebrovascular diseases such as stroke. Consideration of varying methodological approaches and software packages is critical to the calculation of accurate SUVs in cross-sectional and longitudinal patient studies. The aim of this study was to investigate whether or not carotid atherosclerotic plaque SUVs are consistent and reproducible between software packages.
18FDG-PET SUVs of carotids were taken in 101 patients using two different software packages. Quality assurance checks were performed to standardise techniques before commencing the analysis where data from five to seven anatomical sites were measured. A total of ten regions of interest were drawn on each site analysed. Statistical analyses were then performed to compare SUV measurements from the two software packages and to explore reproducibility of measurements. Lastly, the time taken to complete each analysis was measured and compared.
Results
Statistically significant differences in SUV measurements, between the two software packages, ranging from 9 to 21.8% were found depending on ROI location. In 79% (n = 23) of the ROI locations, the differences between the SUV measurements from each software package were found to be statistically significant. The time taken to perform the analyses and export data from the software packages also varied considerably.
Conclusions
This study highlights the importance of standardising all aspects of methodological approaches to ensure accuracy and reproducibility. Physicians must be aware that when a PET-CT data set is analysed, subsequent follow-ups must be verified, if possible, with the same software package or cross-calibration between packages should be performed.
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Impact of X-ray energy on absorbed dose assessed with Monte Carlo simulations in a mouse tumor and in nearest organs irradiated with kilovoltage X-ray beams
Publication date: Available online 28 April 2017
Source:Cancer/Radiothérapie
Author(s): M. Hamdi, M. Mimi, M. Bentourkia
PurposeRadiotherapy treatments to local tumors are always associated with dose deposit in surrounding tissues and even in distant tissues not traversed by the radiation beams. In the present work, we demonstrate by Monte Carlo simulations the impact of radiation energy on absorbed dose in a lung tumor and in other secondary organs in a digital mouse. We also report the energy difference between simulations of monoenergetic and spectral radiations, and between CT-based and atlas-made digital mouse.Materials and methodsWe simulated seven monoenergetic and spectral radiation beams from 50keV (or kVp) to 450keV (or kVp). For each energy mode, the beams were generated along seven angles converging on the tumor. We assessed the absorbed dose in ten volumes including the lungs, the heart and the spine.ResultsThe results showed an increase of absorbed dose as a function of energy with a lowest dose at 100keV. In the secondary organs not traversed by the beams, the spinal cord received doses of 0.78% and 0.07%, and the spinal bone received 2.36% and 0.35% relative to those in the tumor, respectively at 50keV and at 450keV. A region in the heart not traversed by the beams received 2% of the dose to the tumor.ConclusionsThe optimal energy to the tumor with relatively reduced doses to other organs was achieved at energies around 200keV. At these energies, the surrounding of the tumor received lesser doses. Monoenergetic radiations were found to be more appropriate to target the tumor than spectral radiations produced by X-ray tubes, and CT-based digital mouse was more realistic than atlas-based mouse since it accounts for tissue heterogeneity.
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Comparaison de la survie et de la toxicité chronique gastro-intestinale chez les patientes atteintes de cancer du col de l’utérus localement évolué, traité par irradiation classique ou avec modulation d’intensité
Publication date: Available online 28 April 2017
Source:Cancer/Radiothérapie
Author(s): C. Gamelon-Bénichou, S. Oldrini, C. Charra-Brunaud, G. Vogin, J. Salleron, D. Peiffert
Objectif de l'étudeÉvaluer prospectivement la toxicité chronique gastro-intestinale chez les patientes atteintes de cancer du col utérin traité par irradiation classique ou avec modulation d'intensité (RCMI).Patientes et méthodesEntre juin 2005 et septembre 2013, 109 patientes ont bénéficié d'une radiothérapie externe suivie d'une curiethérapie pour un cancer du col utérin à l'institut de cancérologie de Lorraine. Chaque patiente prise en charge par RCMI a été appariée à une patiente traitée par irradiation classique sur les critères suivants : chimiothérapie concomitante, complément de dose ganglionnaire, traitement de l'aire ganglionnaire lombo-aortique, âge. Le recueil de toxicité était prospectif selon la classification du Radiation Therapy Oncology Group. L'objectif principal était de comparer l'incidence de la toxicité digestive chronique entre les deux groupes. L'influence des paramètres dosimétriques sur la toxicité digestive chronique a été étudiée dans un second temps. La comparaison de la toxicité aiguë, la toxicité chronique génito-urinaire, la survie globale et la survie sans récidive constituaient des objectifs secondaires.RésultatsSoixante-six patientes ont pu être appariées. La probabilité de survie globale à 36 mois était de 71 % après irradiation classique contre 73 % après RCMI (p=0,54). Il n'existait significativement pas de différence entre les deux groupes, en termes de toxicité chronique digestive (p=0,17), ni de toxicité aiguë digestive (p=0,6445) et génito-urinaire (p=0,5724). La RCMI épargnait significativement dès 30Gy l'intestin grêle (p==0,0006) et le rectum (p=0,0046), et la vessie à 45Gy (p<0,001). L'incidence de la toxicité génito-urinaire était significativement différente entre les deux groupes (p=0,03), en faveur de la radiothérapie classique.ConclusionNotre étude ne semble pas mettre en évidence de différence significative concernant la survenue de toxicité chronique digestive entre les deux groupes. L'efficacité clinique paraît comparable. Des études avec un effectif plus important et une durée de suivi plus longue doivent être menées.PurposeTo evaluate prospectively chronic gastrointestinal toxicity in patients with cervical cancer treated with conventional irradiation or with intensity-modulated irradiation (IMRT).Patients and methodsBetween June 2005 and September 2013, 109 patients underwent external radiotherapy followed by brachytherapy for cervical cancer at the "Institut de Cancérologie de Lorraine". Each patient receiving IMRT was paired with a patient receiving conventional radiotherapy on the following criteria: concomitant chemotherapy, additional nodal dose, treatment of para-aortic lymph node area, age. The toxicity collection was prospective using the RTOG scale. The main objective was to compare the incidence of gastrointestinal toxicity chronic between the two groups. In a second time, the influence of dosimetric parameters on chronic GI toxicity was investigated. Comparisons of acute toxicity, chronic genitourinary toxicities, overall survival, disease-free survival were secondary objectives.ResultsSixty-six patients were able to be matched. Overall survival at 36 months was 71% in the conventional radiotherapy group against 73% in the IMRT group (P=0.54). There was no significant difference between the two groups in terms of digestive chronic toxicity (P=0.17), nor in terms acute gastrointestinal toxicities (P=0.6445) and genitourinary (P=0.5724). IMRT spared significantly small bowel (P=0.0006) and rectum (P=0.0046) from 30Gy dose, and bladder from 45Gy (P<0.001). The incidence of genitourinary toxicity was significantly different between the two groups (P=0.03) in favor of conventional radiotherapy.ConclusionOur study does not seem to show significant difference in the occurrence of chronic gastrointestinal toxicities between the two groups. Clinical efficacy seems comparable. Larger studies with longer follow-up period should be conducted.
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Impact of X-ray energy on absorbed dose assessed with Monte Carlo simulations in a mouse tumor and in nearest organs irradiated with kilovoltage X-ray beams
Publication date: Available online 28 April 2017
Source:Cancer/Radiothérapie
Author(s): M. Hamdi, M. Mimi, M. Bentourkia
PurposeRadiotherapy treatments to local tumors are always associated with dose deposit in surrounding tissues and even in distant tissues not traversed by the radiation beams. In the present work, we demonstrate by Monte Carlo simulations the impact of radiation energy on absorbed dose in a lung tumor and in other secondary organs in a digital mouse. We also report the energy difference between simulations of monoenergetic and spectral radiations, and between CT-based and atlas-made digital mouse.Materials and methodsWe simulated seven monoenergetic and spectral radiation beams from 50keV (or kVp) to 450keV (or kVp). For each energy mode, the beams were generated along seven angles converging on the tumor. We assessed the absorbed dose in ten volumes including the lungs, the heart and the spine.ResultsThe results showed an increase of absorbed dose as a function of energy with a lowest dose at 100keV. In the secondary organs not traversed by the beams, the spinal cord received doses of 0.78% and 0.07%, and the spinal bone received 2.36% and 0.35% relative to those in the tumor, respectively at 50keV and at 450keV. A region in the heart not traversed by the beams received 2% of the dose to the tumor.ConclusionsThe optimal energy to the tumor with relatively reduced doses to other organs was achieved at energies around 200keV. At these energies, the surrounding of the tumor received lesser doses. Monoenergetic radiations were found to be more appropriate to target the tumor than spectral radiations produced by X-ray tubes, and CT-based digital mouse was more realistic than atlas-based mouse since it accounts for tissue heterogeneity.
http://ift.tt/2pqgEuY
Comparaison de la survie et de la toxicité chronique gastro-intestinale chez les patientes atteintes de cancer du col de l’utérus localement évolué, traité par irradiation classique ou avec modulation d’intensité
Publication date: Available online 28 April 2017
Source:Cancer/Radiothérapie
Author(s): C. Gamelon-Bénichou, S. Oldrini, C. Charra-Brunaud, G. Vogin, J. Salleron, D. Peiffert
Objectif de l'étudeÉvaluer prospectivement la toxicité chronique gastro-intestinale chez les patientes atteintes de cancer du col utérin traité par irradiation classique ou avec modulation d'intensité (RCMI).Patientes et méthodesEntre juin 2005 et septembre 2013, 109 patientes ont bénéficié d'une radiothérapie externe suivie d'une curiethérapie pour un cancer du col utérin à l'institut de cancérologie de Lorraine. Chaque patiente prise en charge par RCMI a été appariée à une patiente traitée par irradiation classique sur les critères suivants : chimiothérapie concomitante, complément de dose ganglionnaire, traitement de l'aire ganglionnaire lombo-aortique, âge. Le recueil de toxicité était prospectif selon la classification du Radiation Therapy Oncology Group. L'objectif principal était de comparer l'incidence de la toxicité digestive chronique entre les deux groupes. L'influence des paramètres dosimétriques sur la toxicité digestive chronique a été étudiée dans un second temps. La comparaison de la toxicité aiguë, la toxicité chronique génito-urinaire, la survie globale et la survie sans récidive constituaient des objectifs secondaires.RésultatsSoixante-six patientes ont pu être appariées. La probabilité de survie globale à 36 mois était de 71 % après irradiation classique contre 73 % après RCMI (p=0,54). Il n'existait significativement pas de différence entre les deux groupes, en termes de toxicité chronique digestive (p=0,17), ni de toxicité aiguë digestive (p=0,6445) et génito-urinaire (p=0,5724). La RCMI épargnait significativement dès 30Gy l'intestin grêle (p==0,0006) et le rectum (p=0,0046), et la vessie à 45Gy (p<0,001). L'incidence de la toxicité génito-urinaire était significativement différente entre les deux groupes (p=0,03), en faveur de la radiothérapie classique.ConclusionNotre étude ne semble pas mettre en évidence de différence significative concernant la survenue de toxicité chronique digestive entre les deux groupes. L'efficacité clinique paraît comparable. Des études avec un effectif plus important et une durée de suivi plus longue doivent être menées.PurposeTo evaluate prospectively chronic gastrointestinal toxicity in patients with cervical cancer treated with conventional irradiation or with intensity-modulated irradiation (IMRT).Patients and methodsBetween June 2005 and September 2013, 109 patients underwent external radiotherapy followed by brachytherapy for cervical cancer at the "Institut de Cancérologie de Lorraine". Each patient receiving IMRT was paired with a patient receiving conventional radiotherapy on the following criteria: concomitant chemotherapy, additional nodal dose, treatment of para-aortic lymph node area, age. The toxicity collection was prospective using the RTOG scale. The main objective was to compare the incidence of gastrointestinal toxicity chronic between the two groups. In a second time, the influence of dosimetric parameters on chronic GI toxicity was investigated. Comparisons of acute toxicity, chronic genitourinary toxicities, overall survival, disease-free survival were secondary objectives.ResultsSixty-six patients were able to be matched. Overall survival at 36 months was 71% in the conventional radiotherapy group against 73% in the IMRT group (P=0.54). There was no significant difference between the two groups in terms of digestive chronic toxicity (P=0.17), nor in terms acute gastrointestinal toxicities (P=0.6445) and genitourinary (P=0.5724). IMRT spared significantly small bowel (P=0.0006) and rectum (P=0.0046) from 30Gy dose, and bladder from 45Gy (P<0.001). The incidence of genitourinary toxicity was significantly different between the two groups (P=0.03) in favor of conventional radiotherapy.ConclusionOur study does not seem to show significant difference in the occurrence of chronic gastrointestinal toxicities between the two groups. Clinical efficacy seems comparable. Larger studies with longer follow-up period should be conducted.
http://ift.tt/2qfaMYn
Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group
Abstract
Background
The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children's Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (>5 WBC with blasts or CNS symptoms) disease at diagnosis.
Methods
We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy.
Results
Young age (P = 0.003), hyperleukocytosis (P < 0.001), and the presence of inversion 16 (P < 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P < 0.001). From diagnosis, event-free survival (EFS) for patients with CNS involvement was significantly worse (P < 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease-free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P < 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome.
Conclusions
CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.
http://ift.tt/2oTRqUH
Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant
Abstract
Cardiomyopathy is common in long-term survivors of pediatric hematopoietic stem cell transplant (HSCT). Events occurring before and after HSCT when combined with specific insults during HSCT likely contribute to long-term risk. Strategies for detecting subclinical cardiomyopathy prior to patients developing overt heart failure are under investigation. Changes in HSCT preparative regimens and cardioprotective medications administered during chemotherapy may alter the risk for cardiomyopathy. Interventions in long-term survivors such as lifestyle modification and cardioactive medications are of increasing importance. Herein we review the causes of cardiac injury, discuss strategies for detection of cardiomyopathy, and evaluate therapeutic options for long-term HSCT survivors.
http://ift.tt/2oTHcDQ
Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement
Abstract
Blinatumomab is a bispecific T-cell engaging αCD19 antibody used in refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again. During this treatment, the leukemia lost CD19 expression as well as nearly all other B-cell markers, while still harboring the initial minimal residual disease marker, and switched to a myeloid phenotype.
http://ift.tt/2oFMnLG
The clinical severity of hemoglobin S/Black (Aγδβ)0-thalassemia
Abstract
Hemoglobin S/Black (Aγδβ)0-thalassemia is a rare sickle cell disease (SCD) variant. On the basis of limited descriptions in the literature, the disease is reported as a mild microcytic anemia with an uncomplicated course. We report the clinical and laboratory data of nine patients whose diagnoses were confirmed by DNA-based techniques. Despite having mild anemia and high fetal hemoglobin level postinfancy, these patients developed many of the classic complications of SCD, including vaso-occlusive crisis, acute chest syndrome, avascular necrosis, and cholelithiasis. On the basis of these findings, we recommend that patients with this rare disorder receive specialized hematology care according to SCD guidelines.
http://ift.tt/2oTVJiI
Clinical outcome of childhood chronic immune thrombocytopenia: A 38-year experience from a single tertiary center in Thailand
Abstract
Background
There is limited information on long-term follow-up and prognostic factors for remission among children diagnosed with chronic immune thrombocytopenia (ITP). The aim of this study was to determine clinical outcomes and factors influencing remission in childhood chronic ITP.
Study Design
The hospital records of children aged 0–15 years diagnosed with chronic ITP were retrospectively reviewed. Kaplan–Meier curves were fit to estimate the median time to complete remission with 95% confidence intervals (CIs). Multivariate Cox proportional hazards regression models were used to identify independent factors for remission.
Results
A total of 113 patients were included in the analysis. The number of children achieving complete remission was 49 (46%) and the median time to remission was 7.1 years (95% CI: 4.8–11.0). The remission rates at 3, 5, 10, and 20 years were 25, 43, 60, and 75%, respectively. Factors influencing remission were platelets >60 × 109/L at the onset of chronic ITP (hazard ratio [HR]: 7.24, 95% CI: 3.0–17.5) and treatment with intravenous immunoglobulin (HR: 0.37, 95% CI: 0.16–0.84). Age, gender, and clinical factors at the time of newly diagnosed ITP including bleeding manifestations, onset of symptoms, and history of preceding infection and vaccination were not predictive of remission.
Conclusion
The spontaneous complete remission rates of chronic ITP were 43 and 60% at 5 and 10 years, respectively, and reached 75% at 20 years. A higher platelet level at diagnosis of chronic ITP and form of treatment were statistically significant indicators for achieving complete remission.
http://ift.tt/2oG4qkZ
Electrophysiological effects of anthracyclines in adult survivors of pediatric malignancy
Abstract
Background
Anthracycline use is limited by cardiotoxicity, including arrhythmias and left ventricular (LV) dysfunction. We aim to characterize the association between electrophysiological changes and LV dysfunction.
Methods
A retrospective chart review was conducted, including all 147 pediatric cancer survivors at our institution over 18 years of age and treated with an anthracycline. One hundred thirty-four patients who had at least one electrocardiogram (ECG) and echocardiogram were analyzed. The association between dysfunction and baseline characteristics, treatment history, and electrocardigraphic parameters were analyzed using multivariable logistic regression. Additionally, a longitudinal generalized estimating equation (GEE) model was used to examine the temporal association between repeated measure corrected QT (QTc) intervals and subsequent LV function.
Results
In our population, 24% of patients had LV dysfunction. The initial posttreatment QTc interval was longer in patients with LV dysfunction (438 ± 35 vs. 420 ± 20 msec, P = 0.002). In logistic regression analysis, QTc interval (P < 0.001) and cumulative radiation dose (P = 0.027) were associated with LV dysfunction. On ECGs performed prior to evidence of LV dysfunction, the QTc was longer than on ECGs preceding a normal echocardiogram (451 ± 32 msec vs. 423 ± 25 msec, P < 0.001). Mean time from QTc ≥ 450 msec to evidence of LV dysfunction was 1.8 ± 2.9 years. In the longitudinal GEE model, QTc prolongation was associated with subsequent decreased fractional shortening.
Conclusions
Among adult survivors of pediatric cancer treated with anthracyclines, prolongation of the QTc interval was associated with subsequent LV dysfunction.
http://ift.tt/2oTFJO1
Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group
Abstract
Background
The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children's Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (>5 WBC with blasts or CNS symptoms) disease at diagnosis.
Methods
We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy.
Results
Young age (P = 0.003), hyperleukocytosis (P < 0.001), and the presence of inversion 16 (P < 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P < 0.001). From diagnosis, event-free survival (EFS) for patients with CNS involvement was significantly worse (P < 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease-free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P < 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome.
Conclusions
CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.
from Cancer via ola Kala on Inoreader http://ift.tt/2oTRqUH
via IFTTT
Cardiotoxicity and cardiomyopathy in children and young adult survivors of hematopoietic stem cell transplant
Abstract
Cardiomyopathy is common in long-term survivors of pediatric hematopoietic stem cell transplant (HSCT). Events occurring before and after HSCT when combined with specific insults during HSCT likely contribute to long-term risk. Strategies for detecting subclinical cardiomyopathy prior to patients developing overt heart failure are under investigation. Changes in HSCT preparative regimens and cardioprotective medications administered during chemotherapy may alter the risk for cardiomyopathy. Interventions in long-term survivors such as lifestyle modification and cardioactive medications are of increasing importance. Herein we review the causes of cardiac injury, discuss strategies for detection of cardiomyopathy, and evaluate therapeutic options for long-term HSCT survivors.
from Cancer via ola Kala on Inoreader http://ift.tt/2oTHcDQ
via IFTTT
Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement
Abstract
Blinatumomab is a bispecific T-cell engaging αCD19 antibody used in refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again. During this treatment, the leukemia lost CD19 expression as well as nearly all other B-cell markers, while still harboring the initial minimal residual disease marker, and switched to a myeloid phenotype.
from Cancer via ola Kala on Inoreader http://ift.tt/2oFMnLG
via IFTTT
The clinical severity of hemoglobin S/Black (Aγδβ)0-thalassemia
Abstract
Hemoglobin S/Black (Aγδβ)0-thalassemia is a rare sickle cell disease (SCD) variant. On the basis of limited descriptions in the literature, the disease is reported as a mild microcytic anemia with an uncomplicated course. We report the clinical and laboratory data of nine patients whose diagnoses were confirmed by DNA-based techniques. Despite having mild anemia and high fetal hemoglobin level postinfancy, these patients developed many of the classic complications of SCD, including vaso-occlusive crisis, acute chest syndrome, avascular necrosis, and cholelithiasis. On the basis of these findings, we recommend that patients with this rare disorder receive specialized hematology care according to SCD guidelines.
from Cancer via ola Kala on Inoreader http://ift.tt/2oTVJiI
via IFTTT
Clinical outcome of childhood chronic immune thrombocytopenia: A 38-year experience from a single tertiary center in Thailand
Abstract
Background
There is limited information on long-term follow-up and prognostic factors for remission among children diagnosed with chronic immune thrombocytopenia (ITP). The aim of this study was to determine clinical outcomes and factors influencing remission in childhood chronic ITP.
Study Design
The hospital records of children aged 0–15 years diagnosed with chronic ITP were retrospectively reviewed. Kaplan–Meier curves were fit to estimate the median time to complete remission with 95% confidence intervals (CIs). Multivariate Cox proportional hazards regression models were used to identify independent factors for remission.
Results
A total of 113 patients were included in the analysis. The number of children achieving complete remission was 49 (46%) and the median time to remission was 7.1 years (95% CI: 4.8–11.0). The remission rates at 3, 5, 10, and 20 years were 25, 43, 60, and 75%, respectively. Factors influencing remission were platelets >60 × 109/L at the onset of chronic ITP (hazard ratio [HR]: 7.24, 95% CI: 3.0–17.5) and treatment with intravenous immunoglobulin (HR: 0.37, 95% CI: 0.16–0.84). Age, gender, and clinical factors at the time of newly diagnosed ITP including bleeding manifestations, onset of symptoms, and history of preceding infection and vaccination were not predictive of remission.
Conclusion
The spontaneous complete remission rates of chronic ITP were 43 and 60% at 5 and 10 years, respectively, and reached 75% at 20 years. A higher platelet level at diagnosis of chronic ITP and form of treatment were statistically significant indicators for achieving complete remission.
from Cancer via ola Kala on Inoreader http://ift.tt/2oG4qkZ
via IFTTT
Electrophysiological effects of anthracyclines in adult survivors of pediatric malignancy
Abstract
Background
Anthracycline use is limited by cardiotoxicity, including arrhythmias and left ventricular (LV) dysfunction. We aim to characterize the association between electrophysiological changes and LV dysfunction.
Methods
A retrospective chart review was conducted, including all 147 pediatric cancer survivors at our institution over 18 years of age and treated with an anthracycline. One hundred thirty-four patients who had at least one electrocardiogram (ECG) and echocardiogram were analyzed. The association between dysfunction and baseline characteristics, treatment history, and electrocardigraphic parameters were analyzed using multivariable logistic regression. Additionally, a longitudinal generalized estimating equation (GEE) model was used to examine the temporal association between repeated measure corrected QT (QTc) intervals and subsequent LV function.
Results
In our population, 24% of patients had LV dysfunction. The initial posttreatment QTc interval was longer in patients with LV dysfunction (438 ± 35 vs. 420 ± 20 msec, P = 0.002). In logistic regression analysis, QTc interval (P < 0.001) and cumulative radiation dose (P = 0.027) were associated with LV dysfunction. On ECGs performed prior to evidence of LV dysfunction, the QTc was longer than on ECGs preceding a normal echocardiogram (451 ± 32 msec vs. 423 ± 25 msec, P < 0.001). Mean time from QTc ≥ 450 msec to evidence of LV dysfunction was 1.8 ± 2.9 years. In the longitudinal GEE model, QTc prolongation was associated with subsequent decreased fractional shortening.
Conclusions
Among adult survivors of pediatric cancer treated with anthracyclines, prolongation of the QTc interval was associated with subsequent LV dysfunction.
from Cancer via ola Kala on Inoreader http://ift.tt/2oTFJO1
via IFTTT
The landscape of BRAF transcript and protein variants in human cancer
Abstract
Background
The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood.
Results
Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3–10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3–10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation.
Conclusions
By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies.
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PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
Abstract
Background
Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death.
Methods
We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.
Results
Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.
Conclusions
PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
from Cancer via ola Kala on Inoreader http://ift.tt/2qo0YYt
via IFTTT
The landscape of BRAF transcript and protein variants in human cancer
Abstract
Background
The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood.
Results
Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3–10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3–10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation.
Conclusions
By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies.
http://ift.tt/2pGPbbv
PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models
Abstract
Background
Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death.
Methods
We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role.
Results
Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing.
Conclusions
PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves clinical evaluation.
http://ift.tt/2qo0YYt
High prevalence of antibodies reacting to mimotopes of Simian virus 40 large T antigen, the oncoprotein, in serum samples of patients affected by non-Hodgkin lymphoma
Abstract
A new immunological investigation was carried out to study the association between non-Hodgkin lymphoma and Simian virus 40 (SV40). To this end, a new indirect ELISA was employed with two mimotopes from SV40 large T antigen (Tag), the viral oncoprotein, to analyse for specific reactions to antibodies in sera from non-Hodgkin lymphoma patients and controls, represented by healthy subjects (HS) and breast carcinoma (BC) patients. This study allowed us to assay a new sera collection from non-Hodgkin lymphoma patients (NHL, n = 254). To verify the association between NHL and SV40 Tag, two totally independent cohorts were analysed: NHL1 n = 150 and NHL2 n = 104. The epidemiological survey included sera from HS1, n = 150; HS2, n = 104 and BC, n = 78. This new indirect ELISA revealed that antibodies against SV40 Tag mimotopes are detectable in NHL1 and NHL2 sera with a prevalence of 37 and 36%, respectively. The prevalence of SV40-antibodies detected in both NHL1 and NHL2 cohorts differs statistically from controls, at 19% for HS1 (p < 0.01), HS2 (p < 0.05) and BC patients (p < 0.05). This study, carried out with an immunological assay with specific Tag oncoprotein mimotopes of Simian virus 40, reports the presence of IgG antibodies against the large Tumour antigen in non-Hodgkin lymphomas for the first time. Our immunological data with two independent NHL cohorts show a statistically significant association between Simian virus 40 Tag and non-Hodgkin lymphoma. These results suggest that SV40-positive non-Hodgkin lymphomas could be treated differently from those tested SV40-negative.
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Management of Grass Pollen Allergy with 5-Grass Pollen Tablet: Results of a 2-Year Real-Life Study
Abstract
Introduction
Allergen immunotherapy is the only treatment option for allergic rhinitis with disease-altering potential. It was the objective of this study to assess the effectiveness and tolerability of a 5-grass pollen tablet in a large population of non-selected grass pollen allergic patients, i.e. patients with different clinical profiles in daily clinical practice.
Methods
In a 2-year, prospective, open-label, multicenter, non-controlled, observational study patients were included from 327 centers across Germany. Rhinoconjunctivitis symptoms, symptomatic medication intake and adverse events were recorded.
Results
A total of 1482 patients aged 4–75 years were included. During the 2-year period of 5-grass pollen tablet therapy, mean rhinoconjunctivitis score decreased significantly in the overall study population by 65.5% (P < 0.001). The percentage of patients taking symptomatic medication decreased from 83.8% to 42.7%. Mean 2-year improvements in rhinoconjunctivitis scores and decreases in the percentage of patients taking symptomatic medication were broadly similar in adults, adolescents and children, in patients with polyallergy versus monoallergy, and in patients with/without asthma. Among polyallergic patients, concomitant application of another specific immunotherapy did not impair treatment outcomes. Adverse drug reactions, predominantly affecting the local application area, occurred in 15.4% of the overall patient population (n = 229). No cases of anaphylaxis or epinephrine use were documented.
Conclusion
This study indicates that sublingual immunotherapy with the 5-grass pollen tablet is well tolerated and provides sustained effectiveness over 2 years in patients with different clinical profiles, producing a significant decrease in allergic symptoms and a reduction in the use of symptomatic medication.
Funding
Stallergenes GmbH.
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RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
Abstract
Introduction
A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.
Methods
Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.
Results
In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.
Conclusion
RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).
Funding
AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.
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Management of Grass Pollen Allergy with 5-Grass Pollen Tablet: Results of a 2-Year Real-Life Study
Abstract
Introduction
Allergen immunotherapy is the only treatment option for allergic rhinitis with disease-altering potential. It was the objective of this study to assess the effectiveness and tolerability of a 5-grass pollen tablet in a large population of non-selected grass pollen allergic patients, i.e. patients with different clinical profiles in daily clinical practice.
Methods
In a 2-year, prospective, open-label, multicenter, non-controlled, observational study patients were included from 327 centers across Germany. Rhinoconjunctivitis symptoms, symptomatic medication intake and adverse events were recorded.
Results
A total of 1482 patients aged 4–75 years were included. During the 2-year period of 5-grass pollen tablet therapy, mean rhinoconjunctivitis score decreased significantly in the overall study population by 65.5% (P < 0.001). The percentage of patients taking symptomatic medication decreased from 83.8% to 42.7%. Mean 2-year improvements in rhinoconjunctivitis scores and decreases in the percentage of patients taking symptomatic medication were broadly similar in adults, adolescents and children, in patients with polyallergy versus monoallergy, and in patients with/without asthma. Among polyallergic patients, concomitant application of another specific immunotherapy did not impair treatment outcomes. Adverse drug reactions, predominantly affecting the local application area, occurred in 15.4% of the overall patient population (n = 229). No cases of anaphylaxis or epinephrine use were documented.
Conclusion
This study indicates that sublingual immunotherapy with the 5-grass pollen tablet is well tolerated and provides sustained effectiveness over 2 years in patients with different clinical profiles, producing a significant decrease in allergic symptoms and a reduction in the use of symptomatic medication.
Funding
Stallergenes GmbH.
http://ift.tt/2qeTri5
RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
Abstract
Introduction
A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.
Methods
Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.
Results
In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.
Conclusion
RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).
Funding
AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript.
http://ift.tt/2pqb6Rg
Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe
Abstract
Leptomeningeal metastases are a late manifestation of systemic cancer which affects up to 10% of patients with solid tumors. Prognosis is poor, and overall survival at 1 year is only approximately 10%. Management depends mainly on general and neurological condition, primary tumor, and patterns of metastasis, notably absence or presence of concurrent systemic or solid brain metastases. Here we set out to characterize current practice patterns of diagnosis and treatment of patients with leptomeningeal metastasis in Europe. We prepared a web-based survey including 25 simple or multiple choices questions on best practice supplemented by eight case vignettes with various diagnosis and management options. The survey was sent to the membership of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group. Between April 7, 2016 and August 8, 2016, 224 colleagues from 26 countries initiated the survey, 115 colleagues completed the whole survey. There were major differences both in the general diagnostic and therapeutic approach, e.g., regarding the use of cerebrospinal fluid (CSF) flow studies, intra-CSF chemotherapy, various types of radiotherapy, and even more so when selecting decisions on diagnostic and therapeutic measures for single case vignettes. Diagnosis and treatment decisions for patients with leptomeningeal metastasis from solid tumors vary widely across Europe. Standardization of diagnosis and evaluation tools as well as controlled studies to improve the level of evidence for all therapeutic approaches to LM are required.
http://ift.tt/2qnSOzu
Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe
Abstract
Leptomeningeal metastases are a late manifestation of systemic cancer which affects up to 10% of patients with solid tumors. Prognosis is poor, and overall survival at 1 year is only approximately 10%. Management depends mainly on general and neurological condition, primary tumor, and patterns of metastasis, notably absence or presence of concurrent systemic or solid brain metastases. Here we set out to characterize current practice patterns of diagnosis and treatment of patients with leptomeningeal metastasis in Europe. We prepared a web-based survey including 25 simple or multiple choices questions on best practice supplemented by eight case vignettes with various diagnosis and management options. The survey was sent to the membership of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group. Between April 7, 2016 and August 8, 2016, 224 colleagues from 26 countries initiated the survey, 115 colleagues completed the whole survey. There were major differences both in the general diagnostic and therapeutic approach, e.g., regarding the use of cerebrospinal fluid (CSF) flow studies, intra-CSF chemotherapy, various types of radiotherapy, and even more so when selecting decisions on diagnostic and therapeutic measures for single case vignettes. Diagnosis and treatment decisions for patients with leptomeningeal metastasis from solid tumors vary widely across Europe. Standardization of diagnosis and evaluation tools as well as controlled studies to improve the level of evidence for all therapeutic approaches to LM are required.
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Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe
Abstract
Leptomeningeal metastases are a late manifestation of systemic cancer which affects up to 10% of patients with solid tumors. Prognosis is poor, and overall survival at 1 year is only approximately 10%. Management depends mainly on general and neurological condition, primary tumor, and patterns of metastasis, notably absence or presence of concurrent systemic or solid brain metastases. Here we set out to characterize current practice patterns of diagnosis and treatment of patients with leptomeningeal metastasis in Europe. We prepared a web-based survey including 25 simple or multiple choices questions on best practice supplemented by eight case vignettes with various diagnosis and management options. The survey was sent to the membership of the European Association of Neuro-Oncology and the European Organisation for Research and Treatment of Cancer Brain Tumor Group. Between April 7, 2016 and August 8, 2016, 224 colleagues from 26 countries initiated the survey, 115 colleagues completed the whole survey. There were major differences both in the general diagnostic and therapeutic approach, e.g., regarding the use of cerebrospinal fluid (CSF) flow studies, intra-CSF chemotherapy, various types of radiotherapy, and even more so when selecting decisions on diagnostic and therapeutic measures for single case vignettes. Diagnosis and treatment decisions for patients with leptomeningeal metastasis from solid tumors vary widely across Europe. Standardization of diagnosis and evaluation tools as well as controlled studies to improve the level of evidence for all therapeutic approaches to LM are required.
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Editorial board
Publication date: March–April 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 2
http://ift.tt/2pdoE47
13 novel putative mutations in ATP7A found in a cohort of 25 Italian families
Abstract
ATP7A is a copper-transporting P-type adenosine triphosphatase whose loss of function leads to the Menkes disease, an X-linked copper metabolism multi-organ disorder (1 in 100.000 births). Here we document our experience with the ATP7A linked diseases in Italy. We analyzed the exonic structure of the ATP7A gene in 25 unrelated Italian families and studied the variants of unknown significance. We identified 22 different DNA alterations, 13 of which first reported in this study. The classical Menkes phenotype was present in 21 of the 25 families and was linked with highly damaging mutations (7 nonsense; 4 frame-shift; 2 small in-frame deletions, 2 splice site alterations, 2 gross deletions, and 1 gross duplication). Of the 4 cases with milder variants of the Menkes disease two had a missense mutation, one a leaky splice site alteration and one a nonsense mutation in exon 22. We determined in silico that all the mutations leading to the classical Menkes disease leave no residual activity of ATP7A including the apparently less severe in-frame deletions. Whereas milder forms of the disease are characterized by mutations that allow a limited residual activity of ATP7A, including the nonsense mutation observed.
http://ift.tt/2qfG3Yn
Effects of repeated restraint stress and WiFi signal exposure on behavior and oxidative stress in rats
Abstract
Today, due to technology development and aversive events of daily life, Human exposure to both radiofrequency and stress is unavoidable. This study investigated the co-exposure to repeated restraint stress and WiFi signal on cognitive function and oxidative stress in brain of male rats. Animals were divided into four groups: Control, WiFi-exposed, restrained and both WiFi-exposed and restrained groups. Each of WiFi exposure and restraint stress occurred 2 h (h)/day during 20 days. Subsequently, various tests were carried out for each group, such as anxiety in elevated plus maze, spatial learning abilities in the water maze, cerebral oxidative stress response and cholinesterase activity in brain and serum. Results showed that WiFi exposure and restraint stress, alone and especially if combined, induced an anxiety-like behavior without impairing spatial learning and memory abilities in rats. At cerebral level, we found an oxidative stress response triggered by WiFi and restraint, per se and especially when combined as well as WiFi-induced increase in acetylcholinesterase activity. Our results reveal that there is an impact of WiFi signal and restraint stress on the brain and cognitive processes especially in elevated plus maze task. In contrast, there are no synergistic effects between WiFi signal and restraint stress on the brain.
http://ift.tt/2oFUpE7
13 novel putative mutations in ATP7A found in a cohort of 25 Italian families
Abstract
ATP7A is a copper-transporting P-type adenosine triphosphatase whose loss of function leads to the Menkes disease, an X-linked copper metabolism multi-organ disorder (1 in 100.000 births). Here we document our experience with the ATP7A linked diseases in Italy. We analyzed the exonic structure of the ATP7A gene in 25 unrelated Italian families and studied the variants of unknown significance. We identified 22 different DNA alterations, 13 of which first reported in this study. The classical Menkes phenotype was present in 21 of the 25 families and was linked with highly damaging mutations (7 nonsense; 4 frame-shift; 2 small in-frame deletions, 2 splice site alterations, 2 gross deletions, and 1 gross duplication). Of the 4 cases with milder variants of the Menkes disease two had a missense mutation, one a leaky splice site alteration and one a nonsense mutation in exon 22. We determined in silico that all the mutations leading to the classical Menkes disease leave no residual activity of ATP7A including the apparently less severe in-frame deletions. Whereas milder forms of the disease are characterized by mutations that allow a limited residual activity of ATP7A, including the nonsense mutation observed.
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Effects of repeated restraint stress and WiFi signal exposure on behavior and oxidative stress in rats
Abstract
Today, due to technology development and aversive events of daily life, Human exposure to both radiofrequency and stress is unavoidable. This study investigated the co-exposure to repeated restraint stress and WiFi signal on cognitive function and oxidative stress in brain of male rats. Animals were divided into four groups: Control, WiFi-exposed, restrained and both WiFi-exposed and restrained groups. Each of WiFi exposure and restraint stress occurred 2 h (h)/day during 20 days. Subsequently, various tests were carried out for each group, such as anxiety in elevated plus maze, spatial learning abilities in the water maze, cerebral oxidative stress response and cholinesterase activity in brain and serum. Results showed that WiFi exposure and restraint stress, alone and especially if combined, induced an anxiety-like behavior without impairing spatial learning and memory abilities in rats. At cerebral level, we found an oxidative stress response triggered by WiFi and restraint, per se and especially when combined as well as WiFi-induced increase in acetylcholinesterase activity. Our results reveal that there is an impact of WiFi signal and restraint stress on the brain and cognitive processes especially in elevated plus maze task. In contrast, there are no synergistic effects between WiFi signal and restraint stress on the brain.
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Long-term results of early adjuvant concurrent chemoradiotherapy for high-risk, early stage uterine cervical cancer patients after radical hysterectomy
Abstract
Background
The aim of the present study was to investigate the long-term survival outcomes and toxicities associated with our experienced early administration of adjuvant concurrent chemoradiotherapy (CCRT).
Methods
Ninety-eight patients with pelvic lymph node metastasis, positive resection margin, and/or parametrial invasion who received adjuvant CCRT between 1995 and 2011 were analyzed retrospectively. The first cycle of platinum-based adjuvant chemotherapy was initiated within 2–3 weeks after surgery (median, 12 days) and continued every 4 weeks for a total of 4 cycles. Adjuvant radiotherapy was performed during the second and third cycles of chemotherapy.
Results
After a median follow-up period of 119 months for survivors, 13 patients (13.3%) experienced recurrence and 11 patients died of cancer during the follow-up period. The 5-year recurrence-free survival and cancer specific survival rates were 87.6% and 90.6%, respectively. Ninety-four patients (95.9%) received ≥3 cycles of chemotherapy. Total radiation dose of ≥45 Gy was delivered in 91 patients (92.9%). Grade 3–4 hematologic and gastrointestinal toxicities developed in 37 (37.8%) and 14 (14.3%) patients during CCRT, respectively.
Conclusion
The present study confirmed the long-term safety and encouraging survival outcomes of early administration of adjuvant CCRT, suggesting the benefits of early time to initiation of adjuvant treatments.
http://ift.tt/2pGuj45
Influence of presence/absence of thyroid gland on the cutoff value for thyroglobulin in lymph-node aspiration to detect metastatic papillary thyroid carcinoma
Abstract
Background
Thyroglobulin measurement with fine-needle aspiration (Tg-FNA) is a sensitive method for detecting metastatic papillary thyroid carcinoma (PTC). However, the diagnostic threshold is not well established and the influence of the thyroid gland on the cutoff value is also controversial. In this study, patients were classified into two groups according to the presence or absence of thyroid tissue, to determine an appropriate cutoff value for clinical practice.
Methods
Patients with a history of thyroid nodules or surgery for PTC and with enlarged cervical lymph nodes on an FNA examination were enrolled for Tg-FNA detection.
Results
One hundred ninety-six lymph nodes (189 patients) were included: 100 from preoperative patients, 49 from patients treated with partial thyroid ablation, and 47 from patients with total thyroid ablation. In 149 lymph nodes from patient with thyroids, the cutoff value for Tg-FNA was 55.99 ng/mL (sensitivity, 95.1%; specificity, 100%), whereas in 47 lymph nodes from patients without a thyroid, it was 9.71 ng/mL (sensitivity, 96.7%; specificity, 100%). Thus, the cutoff value for Tg-FNA was higher in patients with thyroids than in patients without thyroids.
Conclusions
The cutoff value for Tg-FNA is influenced by residual thyroid tissue, and a higher cutoff value is recommended for patients with thyroids than for patients without thyroids.
http://ift.tt/2ptTeHf
KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma
Abstract
It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1/PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1/PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma.
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Long-term results of early adjuvant concurrent chemoradiotherapy for high-risk, early stage uterine cervical cancer patients after radical hysterectomy
Abstract
Background
The aim of the present study was to investigate the long-term survival outcomes and toxicities associated with our experienced early administration of adjuvant concurrent chemoradiotherapy (CCRT).
Methods
Ninety-eight patients with pelvic lymph node metastasis, positive resection margin, and/or parametrial invasion who received adjuvant CCRT between 1995 and 2011 were analyzed retrospectively. The first cycle of platinum-based adjuvant chemotherapy was initiated within 2–3 weeks after surgery (median, 12 days) and continued every 4 weeks for a total of 4 cycles. Adjuvant radiotherapy was performed during the second and third cycles of chemotherapy.
Results
After a median follow-up period of 119 months for survivors, 13 patients (13.3%) experienced recurrence and 11 patients died of cancer during the follow-up period. The 5-year recurrence-free survival and cancer specific survival rates were 87.6% and 90.6%, respectively. Ninety-four patients (95.9%) received ≥3 cycles of chemotherapy. Total radiation dose of ≥45 Gy was delivered in 91 patients (92.9%). Grade 3–4 hematologic and gastrointestinal toxicities developed in 37 (37.8%) and 14 (14.3%) patients during CCRT, respectively.
Conclusion
The present study confirmed the long-term safety and encouraging survival outcomes of early administration of adjuvant CCRT, suggesting the benefits of early time to initiation of adjuvant treatments.
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Influence of presence/absence of thyroid gland on the cutoff value for thyroglobulin in lymph-node aspiration to detect metastatic papillary thyroid carcinoma
Abstract
Background
Thyroglobulin measurement with fine-needle aspiration (Tg-FNA) is a sensitive method for detecting metastatic papillary thyroid carcinoma (PTC). However, the diagnostic threshold is not well established and the influence of the thyroid gland on the cutoff value is also controversial. In this study, patients were classified into two groups according to the presence or absence of thyroid tissue, to determine an appropriate cutoff value for clinical practice.
Methods
Patients with a history of thyroid nodules or surgery for PTC and with enlarged cervical lymph nodes on an FNA examination were enrolled for Tg-FNA detection.
Results
One hundred ninety-six lymph nodes (189 patients) were included: 100 from preoperative patients, 49 from patients treated with partial thyroid ablation, and 47 from patients with total thyroid ablation. In 149 lymph nodes from patient with thyroids, the cutoff value for Tg-FNA was 55.99 ng/mL (sensitivity, 95.1%; specificity, 100%), whereas in 47 lymph nodes from patients without a thyroid, it was 9.71 ng/mL (sensitivity, 96.7%; specificity, 100%). Thus, the cutoff value for Tg-FNA was higher in patients with thyroids than in patients without thyroids.
Conclusions
The cutoff value for Tg-FNA is influenced by residual thyroid tissue, and a higher cutoff value is recommended for patients with thyroids than for patients without thyroids.
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