Hypophosphatasia (HPP) is a rare, inherited metabolic bone disorder characterized by low serum alkaline phosphatase activity and impaired bone mineralization. Clinical manifestations and severity of symptoms vary widely in HPP, ranging from in utero death to isolated dental manifestations in adults. Treatment with enzyme replacement therapy has been reported to improve outcomes in perinatal, infantile, and childhood forms of HPP. Here, we present a case of a boy with poor linear growth, mild limb bowing, and radiographic rickets who was diagnosed with HPP before 6 months of age. Treatment with enzyme replacement therapy was initiated at 7 months of age, after which significant improvements in radiographic findings and linear growth were demonstrated. This case highlights several important challenges in the diagnosis, classification, and management of HPP.
https://ift.tt/2GDJGCD
Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 31 Μαρτίου 2018
Brief Clinical Report: Hypophosphatasia—Diagnostic Considerations and Treatment Outcomes in an Infant
A Rare Case of Lemierre-Like Syndrome: A Case Report and Literature Review
Lemierre's syndrome (LS) is a serious rare complication of oropharyngeal infections. It is characterized by thrombosis of internal jugular vein that rapidly progresses into sepsis and is typically caused by anaerobes. Most of the reported cases have been linked to Fusobacterium necrophorum; however, there are a handful of reported cases due to aerobes. It is primarily the disease of healthy young adults and can present in school-aged children. The early recognition and treatment of this complication results in resolution of the illness; nevertheless, there have been some concerns about chronic venous insufficiency as a long-term complication. We report a case of a 6-year-old boy, who presented with fever and headache with a history of sore throat. His blood culture was positive for group A Streptococcus (GAS) and was subsequently found to have internal jugular vein, sigmoid, and transverse sinus vein thrombosis.
https://ift.tt/2uDRGP6
Infectious Aortitis: A Life-Threatening Endovascular Complication of Nontyphoidal Salmonella Bacteremia
A 65-year-old Japanese man living in the United States presented with pyrexia and chills associated with intermittent lower abdominal and back pain for 5 days. He denied recent travel, rash, diarrhea, or rectal bleeding. Physical examination revealed spiking pyrexia, and routine laboratory tests revealed mild leukocytosis and neutrophilia. Abdominal CT with contrast showed findings highly compatible with aortitis. Comprehensive autoimmune evaluation was negative. Salmonella enterica serotype Enteritidis was isolated from blood cultures. IV antibiotics were administered, but the patient continued to experience low-grade pyrexia and mild leukocytosis, and follow-up abdominal CT showed progressive aortic inflammation. The patient therefore underwent resection of the affected aortic segment with in-situ graft replacement and lifelong suppressive antibiotics. The patient is asymptomatic with no complications at 18 weeks of follow-up. This case report illustrates that patients with infectious aortitis from nontyphoidal Salmonella may (1) present with nonspecific and nonlocalizing symptoms and signs except for sepsis; (2) have diagnostic blood cultures and abdominal CT findings; and (3) typically require aggressive, prolonged IV antibiotic therapy and surgery for potential cure of this life-threatening infection.
https://ift.tt/2J939cF
A Large Grade 5 Mobile Aortic Arch Atheromatous Plaque: Cause of Cerebrovascular Accident
Aortic atheromas (aortic atheromatous plaques) are defined by an irregular thickening of the intima ≥2 mm, and a complex plaque is defined as a protruding atheroma ≥4 mm with or without an attached mobile component. Stroke incidence is approximately 25% in patients with mobile plaques of the aortic arch and 2% in patients with quiescent nonmobile plaques. Antiplatelet agents, oral anticoagulants, and statins have been suggested in the management of atheromas. We present an 80-year-old male, with non-ST-segment elevation myocardial infarction (NSTEMI) and chronic dysarthria, found to have an acute cerebrovascular accident (CVA) secondary to embolism from a large 12 mm aortic arch plaque, treated medically with oral antiplatelet therapy, anticoagulation, and statin therapy.
https://ift.tt/2E91lNd
Prospective Study of Cancer Genetic Variants: Variation in Rate of Reclassification by Ancestry
https://ift.tt/2J8ONcf
Positron Emission Tomography and Computed Tomographic (PET/CT) Imaging for Radiation Therapy Planning in Anal Cancer: a Systematic Review and Meta-analysis
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Per Albertsson, Charlotte Alverbratt, Ann Liljegren, Emil Björkander, Annika Strandell, Ola Samuelsson, Stig Palm, Andreas Hallqvist
To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain.
https://ift.tt/2Ea5BM6
Glucocorticoids as an adjunct to oncologic treatment in solid malignancies – not an innocent bystander
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Corinne Maurice-Dror, Ruth Perets, Gil Bar-Sela
Glucocorticoids are steroidal hormones which exert their action via genomic and non-genomic mechanisms. In the clinical setting, glucocorticoids are utilized for their anti-inflammatory, anti-allergenic and immunomodulatory effects and for their well-established, pro-apoptotic effects on hematological malignancies. In the treatment of solid tumors, glucocorticoids serve primarily for alleviation of tumor- and treatment-related symptoms and in most cases are not considered to have a direct effect on tumor growth and spread. However, significant pre-clinical data suggest that glucocorticoids have diverse effects on tumor progression, both pro- and anti- tumorigenic. In contrast, the clinical data regarding the pro- and anti-tumorigenic effects of glucocorticoids on solid tumors is scarce, and summarized in this review. The following review presents the suggested glucocorticoids mechanism of action and the effects of glucocorticoids on tumor cells, on the tumor microenvironment and on tumor response to cytotoxic therapy, in the pre-clinical and clinical settings.
https://ift.tt/2J8Lf9L
Prediction models for endometrial cancer for the general population or symptomatic women: a systematic review
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Maaike Alblas, Kimberley Velt, Nora Pashayan, Martin Widschwendter, Ewout Steyerberg, Yvonne Vergouwe
ObjectiveTo provide an overview of prediction models for the risk of developing endometrial cancer in women of the general population or for the presence of endometrial cancer in symptomatic women.MethodsWe systematically searched the Embase and Pubmed database until September 2017 for relevant publications. We included studies describing the development, the external validation, or the updating of a multivariable model for predicting endometrial cancer in the general population or symptomatic women.ResultsOut of 2756 references screened, 14 studies were included. We found two prediction models for developing endometrial cancer in the general population (risk models) and one extension. Eight studies described the development of models for symptomatic women (diagnostic models), one comparison of the performance of two diagnostic models and two external validation. Sample size varied from 60 (10 with cancer) to 201,811 (855 with cancer) women. The age of the women was included as a predictor in almost all models. The risk models included epidemiological variables related to the reproductive history of women, hormone use, BMI, and smoking history. The diagnostic models also included clinical predictors, such as endometrial thickness and recurrent bleeding. The concordance statistic (c), assessing the discriminative ability, varied from 0.68 to 0.77 in the risk models and from 0.73 to 0.957 in the diagnostic models. Methodological information was often limited, especially on the handling of missing data, and the selection of predictors. One risk model and four diagnostic models were externally validated.ConclusionsOnly a few models have been developed to predict endometrial cancer in asymptomatic or symptomatic women. The usefulness of most models is unclear considering methodological shortcomings and lack of external validation. Future research should focus on external validation and extension with new predictors or biomarkers, such as genetic and epigenetic markers.
https://ift.tt/2pVERKq
Re-irradiation as salvage treatment in recurrent glioblastoma: a comprehensive literature review to provide practical answers to frequently asked questions
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Silvia Scoccianti, Giulio Francolini, Giulio Alberto Carta, Daniela Greto, Beatrice Detti, Gabriele Simontacchi, Luca Visani, Muhammed Baki, Linda Poggesi, Pierluigi Bonomo, Monica Mangoni, Isacco Desideri, Stefania Pallotta, Lorenzo Livi
The primary aim of this review is to provide practical recommendations in terms of fractionation, dose, constraints and selection criteria to be used in the daily clinical routine.Based on the analysis of the literature reviewed, in order to keep the risk of severe side effects <3,5%, patients should be stratified according to the target volume. Thus, patients should be treated with different fractionation and total EQD2 (<12,5 ml: EQD2 < 65 Gy with radiosurgery; >12,5 ml and <35 ml: EQD2 < 50 Gy with hypofractionated stereotactic radiotherapy; >35 m l and <50 ml: EQD2 < 36 Gy with conventionally fractionated radiotherapy).Concurrent approaches with temozolomide or bevacizumab do not seem to improve the outcomes of reirradiation and may lead to a higher risk of toxicity but these findings need to be confirmed in prospective series.
https://ift.tt/2J9wjIG
Glucocorticoids as an adjunct to oncologic treatment in solid malignancies – not an innocent bystander
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Corinne Maurice-Dror, Ruth Perets, Gil Bar-Sela
Glucocorticoids are steroidal hormones which exert their action via genomic and non-genomic mechanisms. In the clinical setting, glucocorticoids are utilized for their anti-inflammatory, anti-allergenic and immunomodulatory effects and for their well-established, pro-apoptotic effects on hematological malignancies. In the treatment of solid tumors, glucocorticoids serve primarily for alleviation of tumor- and treatment-related symptoms and in most cases are not considered to have a direct effect on tumor growth and spread. However, significant pre-clinical data suggest that glucocorticoids have diverse effects on tumor progression, both pro- and anti- tumorigenic. In contrast, the clinical data regarding the pro- and anti-tumorigenic effects of glucocorticoids on solid tumors is scarce, and summarized in this review. The following review presents the suggested glucocorticoids mechanism of action and the effects of glucocorticoids on tumor cells, on the tumor microenvironment and on tumor response to cytotoxic therapy, in the pre-clinical and clinical settings.
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Positron Emission Tomography and Computed Tomographic (PET/CT) Imaging for Radiation Therapy Planning in Anal Cancer: a Systematic Review and Meta-analysis
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Per Albertsson, Charlotte Alverbratt, Ann Liljegren, Emil Björkander, Annika Strandell, Ola Samuelsson, Stig Palm, Andreas Hallqvist
To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain.
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Prediction models for endometrial cancer for the general population or symptomatic women: a systematic review
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Maaike Alblas, Kimberley Velt, Nora Pashayan, Martin Widschwendter, Ewout Steyerberg, Yvonne Vergouwe
ObjectiveTo provide an overview of prediction models for the risk of developing endometrial cancer in women of the general population or for the presence of endometrial cancer in symptomatic women.MethodsWe systematically searched the Embase and Pubmed database until September 2017 for relevant publications. We included studies describing the development, the external validation, or the updating of a multivariable model for predicting endometrial cancer in the general population or symptomatic women.ResultsOut of 2756 references screened, 14 studies were included. We found two prediction models for developing endometrial cancer in the general population (risk models) and one extension. Eight studies described the development of models for symptomatic women (diagnostic models), one comparison of the performance of two diagnostic models and two external validation. Sample size varied from 60 (10 with cancer) to 201,811 (855 with cancer) women. The age of the women was included as a predictor in almost all models. The risk models included epidemiological variables related to the reproductive history of women, hormone use, BMI, and smoking history. The diagnostic models also included clinical predictors, such as endometrial thickness and recurrent bleeding. The concordance statistic (c), assessing the discriminative ability, varied from 0.68 to 0.77 in the risk models and from 0.73 to 0.957 in the diagnostic models. Methodological information was often limited, especially on the handling of missing data, and the selection of predictors. One risk model and four diagnostic models were externally validated.ConclusionsOnly a few models have been developed to predict endometrial cancer in asymptomatic or symptomatic women. The usefulness of most models is unclear considering methodological shortcomings and lack of external validation. Future research should focus on external validation and extension with new predictors or biomarkers, such as genetic and epigenetic markers.
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Re-irradiation as salvage treatment in recurrent glioblastoma: a comprehensive literature review to provide practical answers to frequently asked questions
Publication date: Available online 31 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Silvia Scoccianti, Giulio Francolini, Giulio Alberto Carta, Daniela Greto, Beatrice Detti, Gabriele Simontacchi, Luca Visani, Muhammed Baki, Linda Poggesi, Pierluigi Bonomo, Monica Mangoni, Isacco Desideri, Stefania Pallotta, Lorenzo Livi
The primary aim of this review is to provide practical recommendations in terms of fractionation, dose, constraints and selection criteria to be used in the daily clinical routine.Based on the analysis of the literature reviewed, in order to keep the risk of severe side effects <3,5%, patients should be stratified according to the target volume. Thus, patients should be treated with different fractionation and total EQD2 (<12,5 ml: EQD2 < 65 Gy with radiosurgery; >12,5 ml and <35 ml: EQD2 < 50 Gy with hypofractionated stereotactic radiotherapy; >35 m l and <50 ml: EQD2 < 36 Gy with conventionally fractionated radiotherapy).Concurrent approaches with temozolomide or bevacizumab do not seem to improve the outcomes of reirradiation and may lead to a higher risk of toxicity but these findings need to be confirmed in prospective series.
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Antenatal non-medical risk assessment and care pathways to improve pregnancy outcomes: a cluster randomised controlled trial
Abstract
Social deprivation negatively affects health outcomes but receives little attention in obstetric risk selection. We investigated whether a combination of (1) risk assessment focused on non-medical risk factors, lifestyle factors, and medical risk factors, with (2) subsequent institution of risk-specific care pathways, and (3) multidisciplinary consultation between care providers from the curative and the public health sector reduced adverse pregnancy outcomes among women in selected urban areas in the Netherlands. We conducted a cluster randomised controlled trial in 14 urban municipalities across the Netherlands. Prior to the randomisation, municipalities were ranked and paired according to their expected proportion of pregnant women at risk for adverse outcomes at birth. The primary outcome was delivery of a preterm and/or small for gestational age (SGA) baby, analysed with multilevel mixed-effects logistic regression analysis adjusting for clustering and individual baseline characteristics. A total of 33 community midwife practices and nine hospitals participated throughout the study. Data from 4302 participants was included in the Intention To Treat (ITT) analysis. The intervention had no demonstrable impact on the primary outcome: adjusted odds ratio (aOR) 1.17 (95% CI 0.84–1.63). Among the secondary outcomes, the intervention improved the detection of threatening preterm delivery and fetal growth restriction during pregnancy [aOR 1.27 (95% CI 1.01–1.61)]. Implementation of additional non-medical risk assessment and preventive strategies into general practices is feasible but did not decrease the incidence of preterm and/or SGA birth in the index pregnancy in deprived urban areas.
Trial registration Netherlands National Trial Register (NTR-3367).
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Antenatal non-medical risk assessment and care pathways to improve pregnancy outcomes: a cluster randomised controlled trial
Abstract
Social deprivation negatively affects health outcomes but receives little attention in obstetric risk selection. We investigated whether a combination of (1) risk assessment focused on non-medical risk factors, lifestyle factors, and medical risk factors, with (2) subsequent institution of risk-specific care pathways, and (3) multidisciplinary consultation between care providers from the curative and the public health sector reduced adverse pregnancy outcomes among women in selected urban areas in the Netherlands. We conducted a cluster randomised controlled trial in 14 urban municipalities across the Netherlands. Prior to the randomisation, municipalities were ranked and paired according to their expected proportion of pregnant women at risk for adverse outcomes at birth. The primary outcome was delivery of a preterm and/or small for gestational age (SGA) baby, analysed with multilevel mixed-effects logistic regression analysis adjusting for clustering and individual baseline characteristics. A total of 33 community midwife practices and nine hospitals participated throughout the study. Data from 4302 participants was included in the Intention To Treat (ITT) analysis. The intervention had no demonstrable impact on the primary outcome: adjusted odds ratio (aOR) 1.17 (95% CI 0.84–1.63). Among the secondary outcomes, the intervention improved the detection of threatening preterm delivery and fetal growth restriction during pregnancy [aOR 1.27 (95% CI 1.01–1.61)]. Implementation of additional non-medical risk assessment and preventive strategies into general practices is feasible but did not decrease the incidence of preterm and/or SGA birth in the index pregnancy in deprived urban areas.
Trial registration Netherlands National Trial Register (NTR-3367).
https://ift.tt/2GXX4Pq
Antenatal non-medical risk assessment and care pathways to improve pregnancy outcomes: a cluster randomised controlled trial
Abstract
Social deprivation negatively affects health outcomes but receives little attention in obstetric risk selection. We investigated whether a combination of (1) risk assessment focused on non-medical risk factors, lifestyle factors, and medical risk factors, with (2) subsequent institution of risk-specific care pathways, and (3) multidisciplinary consultation between care providers from the curative and the public health sector reduced adverse pregnancy outcomes among women in selected urban areas in the Netherlands. We conducted a cluster randomised controlled trial in 14 urban municipalities across the Netherlands. Prior to the randomisation, municipalities were ranked and paired according to their expected proportion of pregnant women at risk for adverse outcomes at birth. The primary outcome was delivery of a preterm and/or small for gestational age (SGA) baby, analysed with multilevel mixed-effects logistic regression analysis adjusting for clustering and individual baseline characteristics. A total of 33 community midwife practices and nine hospitals participated throughout the study. Data from 4302 participants was included in the Intention To Treat (ITT) analysis. The intervention had no demonstrable impact on the primary outcome: adjusted odds ratio (aOR) 1.17 (95% CI 0.84–1.63). Among the secondary outcomes, the intervention improved the detection of threatening preterm delivery and fetal growth restriction during pregnancy [aOR 1.27 (95% CI 1.01–1.61)]. Implementation of additional non-medical risk assessment and preventive strategies into general practices is feasible but did not decrease the incidence of preterm and/or SGA birth in the index pregnancy in deprived urban areas.
Trial registration Netherlands National Trial Register (NTR-3367).
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Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner
Abstract
Purpose
At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive.
Methods
In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC.
Results
Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment.
Conclusions
In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance.
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"Anticancer Res"[jour]; +77 new citations
77 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/03/31
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
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Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner
Abstract
Purpose
At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive.
Methods
In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC.
Results
Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment.
Conclusions
In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance.
https://ift.tt/2uzYn4H
Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner
Abstract
Purpose
At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive.
Methods
In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC.
Results
Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment.
Conclusions
In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance.
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Hypothesis-free screening of large administrative databases for unsuspected drug-outcome associations
Abstract
Active surveillance for unknown or unsuspected adverse drug effects may be carried out by applying epidemiological techniques to large administrative databases. Self-controlled designs, like the symmetry design, have the advantage over conventional design of adjusting for confounders that are stable over time. The aim of this paper was to describe the output of a comprehensive open-ended symmetry analysis of a large dataset. All drug dispensings and all secondary care contacts in Denmark during the period 1995–2012 for persons born before 1950 were analyzed by a symmetry design. We analyzed all drug–drug sequences and all drug–disease sequences occurring during the study period. The identified associations were ranked according to the number of outcomes that potentially could be attributed to the exposure. In the main analysis, 29,891,212 incident drug therapies, and 21,300,000 incident diagnoses were included. Out of 186,758 associations tested in the main analysis, 43,575 (23.3%) showed meaningful effect size. For the top 200 drug–drug associations, 47% represented unknown associations, 24% represented known adverse drug reactions, 30% were explained by mutual indication or reverse causation. For the top 200 drug–disease associations the proportions were 31, 15, and 55%, respectively. Screening by symmetry analysis can be a useful starting point for systematic pharmacovigilance activities if coupled with a systematic post-hoc review of signals.
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Correction to: Esophagus perforation and myocardial penetration caused by swallowing of a foreign body leading to a misdiagnosis of acute coronary syndrome: a case report
In the publication of this article [1], the Acknowledgements section was missing.
https://ift.tt/2pPGEBC
Coronary artery fistula with associated Takotsubo cardiomyopathy: a case report
Coronary artery fistula, first described by Krause in 1865, is an abnormal communication between the coronary artery and one of the four chambers of the heart or one of the great vessels. The communications ar...
https://ift.tt/2GpAtuh
Hypothesis-free screening of large administrative databases for unsuspected drug-outcome associations
Abstract
Active surveillance for unknown or unsuspected adverse drug effects may be carried out by applying epidemiological techniques to large administrative databases. Self-controlled designs, like the symmetry design, have the advantage over conventional design of adjusting for confounders that are stable over time. The aim of this paper was to describe the output of a comprehensive open-ended symmetry analysis of a large dataset. All drug dispensings and all secondary care contacts in Denmark during the period 1995–2012 for persons born before 1950 were analyzed by a symmetry design. We analyzed all drug–drug sequences and all drug–disease sequences occurring during the study period. The identified associations were ranked according to the number of outcomes that potentially could be attributed to the exposure. In the main analysis, 29,891,212 incident drug therapies, and 21,300,000 incident diagnoses were included. Out of 186,758 associations tested in the main analysis, 43,575 (23.3%) showed meaningful effect size. For the top 200 drug–drug associations, 47% represented unknown associations, 24% represented known adverse drug reactions, 30% were explained by mutual indication or reverse causation. For the top 200 drug–disease associations the proportions were 31, 15, and 55%, respectively. Screening by symmetry analysis can be a useful starting point for systematic pharmacovigilance activities if coupled with a systematic post-hoc review of signals.
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Hypothesis-free screening of large administrative databases for unsuspected drug-outcome associations
Abstract
Active surveillance for unknown or unsuspected adverse drug effects may be carried out by applying epidemiological techniques to large administrative databases. Self-controlled designs, like the symmetry design, have the advantage over conventional design of adjusting for confounders that are stable over time. The aim of this paper was to describe the output of a comprehensive open-ended symmetry analysis of a large dataset. All drug dispensings and all secondary care contacts in Denmark during the period 1995–2012 for persons born before 1950 were analyzed by a symmetry design. We analyzed all drug–drug sequences and all drug–disease sequences occurring during the study period. The identified associations were ranked according to the number of outcomes that potentially could be attributed to the exposure. In the main analysis, 29,891,212 incident drug therapies, and 21,300,000 incident diagnoses were included. Out of 186,758 associations tested in the main analysis, 43,575 (23.3%) showed meaningful effect size. For the top 200 drug–drug associations, 47% represented unknown associations, 24% represented known adverse drug reactions, 30% were explained by mutual indication or reverse causation. For the top 200 drug–disease associations the proportions were 31, 15, and 55%, respectively. Screening by symmetry analysis can be a useful starting point for systematic pharmacovigilance activities if coupled with a systematic post-hoc review of signals.
https://ift.tt/2J9CL2k
Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
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Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
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MiR-422a weakened breast cancer stem cells properties by targeting PLP2
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Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
https://ift.tt/2pYofmf
Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
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Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
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"Anticancer Res"[jour]; +77 new citations
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Induction of a central memory and stem cell memory phenotype in functionally active CD4 + and CD8 + CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19 + acute lymphoblastic leukemia
Abstract
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co-inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-γ, TNF-α and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype.
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The role of genomic profiling in adolescents and young adults (AYAs) with advanced cancer participating in phase I clinical trials
Publication date: May 2018
Source:European Journal of Cancer, Volume 95
Author(s): Terri Patricia McVeigh, Raghav Sundar, Nikolaos Diamantis, Stan B. Kaye, Udai Banerji, Juanita S. Lopez, Johann de Bono, Winette T.A. van der Graaf, Angela J. George
IntroductionAdolescents and young adults (AYAs) diagnosed with cancer between ages 15–39 years may harbour germline variants associated with cancer predisposition. Such variants represent putative therapeutic targets, as may somatic variants in the tumour. Germline and tumour molecular profiling is increasingly utilised to facilitate personalisation of cancer treatment in such individuals.AimConsidering AYAs with advanced solid tumours managed in a specialist drug development unit (DDU), the aims of this study were to investigate the use and impact of:1. Germline genetic assessment.2. Tumour molecular profiling.MethodsAYAs treated in the DDU at the Royal Marsden Hospital between 2002 and 2016 were identified from departmental databases. Data regarding clinicopathological features, clinical assessments and germline and tumour genetic testing were retrieved by chart review.ResultsThe study cohort included 219 AYAs. Common cancer types included sarcoma (41, 19%); cervical (27, 12%); breast (25, 11%); ovarian (23, 11%) and colorectal (21, 10%) cancers. Germline testing was undertaken in 34 (16%) patients, 22 of whom carried a pathogenic variant. Using current testing criteria, an additional 32 (15%) would be eligible for germline testing based on their personal history of cancer alone. Tumour testing was undertaken in 46 (21%) individuals. Somatic mutations were commonly identified in TP53 13 (28%); PIK3CA (8, 18%); KRAS (4, 9%) and MET 5 (11%).DiscussionA significant proportion of AYAs with advanced cancer have targetable somatic or germline mutations. Consideration of familial risk factors and inclusion of germline testing wherever appropriate can complement tumour testing to optimise patient management and inform management of at-risk relatives.
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Issue Information ‐ TOC
Journal of Surgical Oncology, Volume 117, Issue 4, Page 540-544, March 15, 2018.
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Issue Information ‐ Ed Board
Journal of Surgical Oncology, Volume 117, Issue 4, Page 539-539, March 15, 2018.
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Cover Image, Volume 117, Number 4, March 15, 2018
Journal of Surgical Oncology, Volume 117, Issue 4, Page i-i, March 15, 2018.
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Totally minimally invasive esophagectomy after neoadjuvant chemoradiotherapy: Long‐term oncologic outcomes
Journal of Surgical Oncology, Volume 117, Issue 4, Page 651-658, March 15, 2018.
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