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.
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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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.
https://ift.tt/2Ilc8X8
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.
https://ift.tt/2pTpEKN
Παρασκευή 30 Μαρτίου 2018
Issue Information ‐ TOC
Journal of Surgical Oncology, Volume 117, Issue 4, Page 540-544, March 15, 2018.
https://ift.tt/2GqNgwr
Cover Image, Volume 117, Number 4, March 15, 2018
Journal of Surgical Oncology, Volume 117, Issue 4, Page i-i, March 15, 2018.
https://ift.tt/2Ilc8X8
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.
https://ift.tt/2pTpEKN
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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Anti‐thymocyte globulin improves survival free from relapse and graft‐versus‐host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia‐negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT
Cancer, EarlyView.
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The pot dealer state harms patients with cancer
Cancer, EarlyView.
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Reply to The pot dealer state harms patients with cancer
Cancer, EarlyView.
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HOTAIR gene polymorphisms contribute to increased neuroblastoma susceptibility in Chinese children
Cancer, EarlyView.
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Anti‐thymocyte globulin improves survival free from relapse and graft‐versus‐host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia‐negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT
Cancer, EarlyView.
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HOTAIR gene polymorphisms contribute to increased neuroblastoma susceptibility in Chinese children
Cancer, EarlyView.
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Precision medicine becomes reality—tumor type-agnostic therapy
Abstract
Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next-generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.
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Selection of candidates for surgery as local therapy among early-stage small cell lung cancer patients: a population-based analysis
Abstract
Background
Surgery and radiotherapy are considered local therapies for small cell lung cancer (SCLC). The present study aimed to select candidates for surgery as local therapy among patients with stage I or II SCLC, based on the eighth edition of the TNM classification for lung cancer.
Methods
Patients diagnosed with SCLC between 2004 and 2013 were selected from the Surveillance, Epidemiology, And End Results database. The TNM stage of SCLC in these patients was re-classified according to the eighth edition of the TNM classification for lung cancer. Patients with stage I or II SCLC were included in the present study. Overall survival (OS) and lung cancer-specific survival (LCSS) were separately compared in the different TNM stages between patients who received surgery and radiotherapy as local therapy. Multivariate analysis was applied to evaluate multiple factors associated with survival.
Results
Among the 2129 patients included in the present study, 387 (18.2%) received surgery, 1032 (48.5%) underwent radiotherapy as local therapy, 154 (7.2%) underwent surgery and radiotherapy, and 556 (26.1%) did not undergo either surgery or radiotherapy. Among patients with T1-2N0 (tumor size ≤ 50 mm without positive lymph nodes) disease, patients who underwent surgery had higher 5-year OS and LCSS rates than patients who received radiotherapy (T1N0: 46.0% vs. 23.8%, P < 0.001, and 58.4% vs. 36.4%, P < 0.001, respectively; T2N0: 42.6% vs. 24.7%, P = 0.004, and 48.8% vs. 31.3%, P = 0.011, respectively). Multivariate analysis results revealed that surgery was associated with low risk of death. However, among T3N0 or T1-2N1 (stage IIB) SCLC patients, patients who underwent surgery did not have higher 5-year OS and LCSS rates than patients who received radiotherapy (T3N0: 16.2% vs. 26.5%, P = 0.085, and 28.7% vs. 30.9%, P = 0.372, respectively; T1-2N1: 20.3% vs. 29.0%, P = 0.146, and 25.6% vs. 35.5%, P = 0.064, respectively).
Conclusions
Based on the assumption that the overwhelming majority of stage I or II SCLC patients who underwent surgery or radiotherapy also received certain types of systemic therapy, only patients with T1-2N0 SCLC may benefit from surgery as local therapy. Patients with T3N0 or T1-2N1 SCLC may consider radiotherapy as local therapy.
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Precision medicine becomes reality—tumor type-agnostic therapy
Abstract
Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next-generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.
https://ift.tt/2GHadyD
Selection of candidates for surgery as local therapy among early-stage small cell lung cancer patients: a population-based analysis
Abstract
Background
Surgery and radiotherapy are considered local therapies for small cell lung cancer (SCLC). The present study aimed to select candidates for surgery as local therapy among patients with stage I or II SCLC, based on the eighth edition of the TNM classification for lung cancer.
Methods
Patients diagnosed with SCLC between 2004 and 2013 were selected from the Surveillance, Epidemiology, And End Results database. The TNM stage of SCLC in these patients was re-classified according to the eighth edition of the TNM classification for lung cancer. Patients with stage I or II SCLC were included in the present study. Overall survival (OS) and lung cancer-specific survival (LCSS) were separately compared in the different TNM stages between patients who received surgery and radiotherapy as local therapy. Multivariate analysis was applied to evaluate multiple factors associated with survival.
Results
Among the 2129 patients included in the present study, 387 (18.2%) received surgery, 1032 (48.5%) underwent radiotherapy as local therapy, 154 (7.2%) underwent surgery and radiotherapy, and 556 (26.1%) did not undergo either surgery or radiotherapy. Among patients with T1-2N0 (tumor size ≤ 50 mm without positive lymph nodes) disease, patients who underwent surgery had higher 5-year OS and LCSS rates than patients who received radiotherapy (T1N0: 46.0% vs. 23.8%, P < 0.001, and 58.4% vs. 36.4%, P < 0.001, respectively; T2N0: 42.6% vs. 24.7%, P = 0.004, and 48.8% vs. 31.3%, P = 0.011, respectively). Multivariate analysis results revealed that surgery was associated with low risk of death. However, among T3N0 or T1-2N1 (stage IIB) SCLC patients, patients who underwent surgery did not have higher 5-year OS and LCSS rates than patients who received radiotherapy (T3N0: 16.2% vs. 26.5%, P = 0.085, and 28.7% vs. 30.9%, P = 0.372, respectively; T1-2N1: 20.3% vs. 29.0%, P = 0.146, and 25.6% vs. 35.5%, P = 0.064, respectively).
Conclusions
Based on the assumption that the overwhelming majority of stage I or II SCLC patients who underwent surgery or radiotherapy also received certain types of systemic therapy, only patients with T1-2N0 SCLC may benefit from surgery as local therapy. Patients with T3N0 or T1-2N1 SCLC may consider radiotherapy as local therapy.
https://ift.tt/2GnwZZ4
Loss of NF-{kappa}B1 Promotes Inflammation and Immune Checkpoint Regulators [Research Watch]
Polymorphisms that reduce NF-B1 in epithelial and hematopoietic cells promote gastric cancer.
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Increasing Fc{gamma}R Binding Activity May Enhance Anti-CTLA4 Efficacy [Research Watch]
Anti-CTLA4 antibodies induce an FcR-dependent depletion of Tregs to promote tumor rejection.
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Inhibiting PTPN12-Regulated RTKs May Be Therapeutic in TNBC [Research Watch]
PTPN12 deficiency may confer sensitivity to tyrosine kinase inhibitor combinations in TNBC.
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LHPP Is a Histidine Phosphatase and a Tumor Suppressor [Research Watch]
Deregulated histidine phosphorylation may promote tumorigenesis in hepatocellular carcinoma (HCC).
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Machine Learning Improves Diagnosis of CNS Cancers [News in Brief]
Algorithm spots patterns in genome-wide methylation profiles to help classify brain and spinal cord tumors.
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A Review of Promising Natural Chemopreventive Agents for Head and Neck Cancer
Head and neck squamous cell carcinoma (HNSCC) accounts for 300,000 deaths per year worldwide and overall survival rates have shown little improvement over the past three decades. Current treatment methods including surgery, chemotherapy, and radiotherapy leave patients with secondary morbidities. Thus, treatment of HNSCC may benefit from exploration of natural compounds as chemopreventive agents. With excellent safety profiles, reduced toxicities, antioxidant properties, and general acceptance for use as dietary supplements, natural compounds are viewed as a desirable area of investigation for chemoprevention. Though most of the field is early in development, numerous studies display the potential utility of natural compounds against HNSCC. These compounds face additional challenges such as low bioavailability for systemic delivery, potential toxicities when consumed in pharmacological doses, and acquired resistance. However, novel delivery vehicles and synthetic analogs have shown overcome some of these challenges. This review covers eleven promising natural compounds in the chemoprevention of HNSCC including vitamin A, curcumin, isothiocyanate, green tea, luteolin, resveratrol, genistein, lycopene, bitter melon, withaferin A, and guggulsterone. The review discusses the therapeutic potential and associated challenges of these agents in the chemopreventive efforts against HNSCC.
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Tumour-derived GM-CSF promotes granulocyte immunosuppression in mesothelioma patients
Purpose: The cross talk between tumour cells, myeloid cells, and T cells play a critical role in tumour pathogenesis and response to immunotherapies. Although the aetiology of mesothelioma is well understood the impact of mesothelioma on the surrounding immune microenvironment is less well studied. In this study the effect of the mesothelioma microenvironment on circulating and infiltrating granulocytes and T cells is investigated. Experimental Design: Tumour and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T cell suppression. Co-cultures of granulocytes, mesothelioma cells, T cells were used to identify the mechanism of T cell inhibition. Results: Analysis of tumours showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T cell proliferation and activation. Characterisation of the blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared to healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of Reactive Oxygen Species (ROS) from granulocytes, resulting in T cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumours express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralising antibody, or ROS inhibition, restored T cell proliferation suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients. Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma and the immune micro-environment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy.
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SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy
Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by Flow Cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-L-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells. Results: SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Conclusions:Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy.
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Tumour-derived GM-CSF promotes granulocyte immunosuppression in mesothelioma patients
Purpose: The cross talk between tumour cells, myeloid cells, and T cells play a critical role in tumour pathogenesis and response to immunotherapies. Although the aetiology of mesothelioma is well understood the impact of mesothelioma on the surrounding immune microenvironment is less well studied. In this study the effect of the mesothelioma microenvironment on circulating and infiltrating granulocytes and T cells is investigated. Experimental Design: Tumour and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T cell suppression. Co-cultures of granulocytes, mesothelioma cells, T cells were used to identify the mechanism of T cell inhibition. Results: Analysis of tumours showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T cell proliferation and activation. Characterisation of the blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared to healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of Reactive Oxygen Species (ROS) from granulocytes, resulting in T cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumours express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralising antibody, or ROS inhibition, restored T cell proliferation suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients. Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma and the immune micro-environment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy.
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Renal failure in pediatric Castleman disease: Four French cases with thrombotic microangiopathy
Pediatric Blood &Cancer, EarlyView.
https://ift.tt/2pXLgFV
Parent understanding of the risk of future limitations secondary to pediatric cancer treatment
Pediatric Blood &Cancer, EarlyView.
https://ift.tt/2Ih3bOm
Comment on: Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia
Pediatric Blood &Cancer, EarlyView.
https://ift.tt/2pXLehh
Renal failure in pediatric Castleman disease: Four French cases with thrombotic microangiopathy
Pediatric Blood &Cancer, EarlyView.
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Parent understanding of the risk of future limitations secondary to pediatric cancer treatment
Pediatric Blood &Cancer, EarlyView.
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Phase I trial of the mTOR inhibitor everolimus in combination with multi‐agent chemotherapy in relapsed childhood acute lymphoblastic leukemia
Pediatric Blood &Cancer, EarlyView.
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Three-dimensional cluster formation and structure in heterogeneous dose distribution of intensity modulated radiation therapy
To investigate three-dimensional cluster structure and its correlation to clinical endpoint in heterogeneous dose distributions from intensity modulated radiation therapy.
https://ift.tt/2GDWTLt
Programmed death‐ligand 1 (PD‐L1) expression in pleomorphic carcinoma of the lung
Journal of Surgical Oncology, EarlyView.
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Intraoperative identification and definition of “functional” lymphatic collecting vessels for supermicrosurgical lymphatico‐venous anastomosis in treating lymphedema patients
Journal of Surgical Oncology, EarlyView.
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In response to: Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities
Journal of Surgical Oncology, EarlyView.
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Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities
Journal of Surgical Oncology, EarlyView.
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Intraoperative identification and definition of “functional” lymphatic collecting vessels for supermicrosurgical lymphatico‐venous anastomosis in treating lymphedema patients
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2pRIfqm
Programmed death‐ligand 1 (PD‐L1) expression in pleomorphic carcinoma of the lung
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2IgcrlL
Breast cancer subtypes and local recurrence rate after surgery for bone metastasis to the extremities
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2pRyPeE
In response to: Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2uBTzvL
Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2pRScnP
Adiponectin Reverses the Proliferative Effects of Estradiol and IGF-1 in Human Epithelial Ovarian Cancer Cells by Downregulating the Expression of Their Receptors
Abstract
The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17β-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells.
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Adiponectin Reverses the Proliferative Effects of Estradiol and IGF-1 in Human Epithelial Ovarian Cancer Cells by Downregulating the Expression of Their Receptors
Abstract
The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17β-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells.
https://ift.tt/2GGtlg8
Intraoperative identification and definition of “functional” lymphatic collecting vessels for supermicrosurgical lymphatico‐venous anastomosis in treating lymphedema patients
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2pRIfqm
Programmed death‐ligand 1 (PD‐L1) expression in pleomorphic carcinoma of the lung
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2IgcrlL
Breast cancer subtypes and local recurrence rate after surgery for bone metastasis to the extremities
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2pRyPeE
In response to: Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2uBTzvL
Long‐term overall survival of patients diagnosed with pure tubular carcinoma of the breast might be affected by increased co‐morbidities
Journal of Surgical Oncology, EarlyView.
https://ift.tt/2pRScnP
Trps1 is associated with the multidrug resistance of lung cancer cell by regulating MGMT gene expression
Cancer Medicine, EarlyView.
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Trps1 is associated with the multidrug resistance of lung cancer cell by regulating MGMT gene expression
Cancer Medicine, EarlyView.
https://ift.tt/2pRhhiE
Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies
Abstract
Purpose
The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.
Methods
In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.
Results
A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were − 0.529 ms (90% CI − 6.621, 5.562) on day 1 and − 9.202 ms (90% CI − 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI − 1.343, 2.412) and 1.16 (90% CI − 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.
Conclusions
Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.
Registration
The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.
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Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies
Abstract
Purpose
The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.
Methods
In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.
Results
A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were − 0.529 ms (90% CI − 6.621, 5.562) on day 1 and − 9.202 ms (90% CI − 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI − 1.343, 2.412) and 1.16 (90% CI − 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.
Conclusions
Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.
Registration
The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.
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Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies
Abstract
Purpose
The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed.
Methods
In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory.
Results
A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were − 0.529 ms (90% CI − 6.621, 5.562) on day 1 and − 9.202 ms (90% CI − 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI − 1.343, 2.412) and 1.16 (90% CI − 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals.
Conclusions
Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters.
Registration
The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.
https://ift.tt/2pUJaFJ
Clinical importance of DNA repair in sporadic colorectal cancer
Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Gustavo A. Laporte, Natalia M. Leguisamo, Antonio N. Kalil, Jenifer Saffi
Colorectal cancer (CRC) is the third major cause of cancer-related deaths worldwide. However, despite the scientific efforts to provide a molecular classification to improve CRC clinical practice management, prognosis and therapeutic decision are still strongly dependent on the TNM staging system. Mismatch repair system deficiencies can occur in many organs, but it is mainly a hallmark of CRC influencing clinical outcomes and response to therapy. This review will discuss the effect of the modulation of other DNA repair pathways (direct, excision and double strand break repairs) in the clinical and pathological aspects of colorectal cancer and its potential as prognostic and predictive biomarkers.
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Targeting the tumor promoting effects of adenosine in chronic lymphocytic leukemia
Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Yiqing Cai, Lili Feng, Xin Wang
Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms. In this review, we focused on the multiple functions and related mechanisms of ADO signaling in CLL generation and progression.
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Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system
Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Hani M Babiker, Ali McBride, Michael Newton, Leigh M. Boehmer, Adrienne Goeller Drucker, Mollie Gowan, Manouchkathe Cassagnol, Todd D. Camenisch, Faiz Anwer, James M. Hollands
Cardiotoxic effects of chemotherapy and targeted drugs are ubiquitous and challenging in the field of oncology therapeutics. The broad spectrum of toxicities ranging from ischemic, hypertensive, cardiomyopathic, and arrhythmic complications can present as a significant challenge for clinicians treating cancer patients. If early diagnosis and intervention of cardiotoxic complications is missed, this can lead to delay or abrogation of planned treatment, which can potentially culminate to significant morbidity due to not only the cardiotoxic complications but also the progression of cancer. Hence, full knowledge of cardiovascular complications of chemotherapeutic agents, essential diagnostics tests to order, and appropriate management is paramount to oncologist, oncology pharmacists, and scientific clinical investigators. The aforementioned is particularly true in the current oncology era of plenteous early clinical trials studying several pathway/molecular-targeting agents with an increased cardiotoxic potential and the rapid expedited approval of those drugs by the FDA. Herein, we present a review discussing cardiotoxic effects of drugs and guidelines for management of the toxicities to assist the medical field in general managing patients with cancer.
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Going the distance: are we losing patients along the multiple myeloma treatment pathway?
Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Evangelos Terpos, Florence Suzan, Hartmut Goldschmidt
Despite data suggesting that individuals with multiple myeloma can benefit from receiving several lines of therapy, and guidelines recommending treatment after relapse, a recent European patient chart review found that only 61% of patients receive second-line treatment. The review found that factors such as old age and previous adverse events lead to physicians deciding not to treat after relapse. However, given the large number of regimens available, treatment can be tailored to individual patients' needs and supportive care measures can help with the management of adverse effects. If approved therapies are not suitable for a patient, guidelines recommend registration in a clinical trial, yet only 7% of patients in the review were participating in such studies. A need for better education on the range of treatments available and their risk–benefit profiles is suggested. Access to new drugs should be examined to maximise the number of patients benefitting from them.
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Role of Bevacizumab in Uterine Leiomyosarcoma
Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Giorgio Bogani, Antonino Ditto, Fabio Martineli, Mauro Signorelli, Valentina Chiappa, Caterina Fonatella, Roberta Sanfilippo, Umberto Leone Roberti Maggiore, Simone Ferrero, Domenica Lorusso, Francesco Raspagliesi
In the recent years, angiogenetic inhibitors have emerged for the treatment of several malignancies. In particular, bevacizumab has proved to be effective in many types of cancers (including sarcoma), but the limitations of antiangiogenic therapy have been shown in practice. Here, we sought to review the current evidence on the role and efficacy of bevacizumab in patients affected by uterine leiomyosarcoma. On April 2017, Literature was searched in order to identify studies reporting outcomes of patients affected either by early stage or advanced/recurred uterine leiomyosarcoma undergoing treatment with bevacizumab, alone or in combination with other chemotherapeutic regimens. Searching the literature data of 69 patients affected by metastatic, unresectable uterine leiomyosarcoma were retrieved; on the contrary, no data regarding the use of bevacizumab in patients with early-stage uterine leiomyosarcoma was published. Current evidence suggested that the addiction of bevacizumab to standard treatment modality does not increase grade 3 or worse toxicity (assessed by CTCAE). Pooled data regarding response rate suggested that 35%, 28%, 26% and 11% of patients experienced objective cure (complete + partial response), stable disease, progressive disease and unknown response, respectively. Data from the only one randomized controlled trial suggested that objective cure rate does not differ from standard chemotherapy treatment, thus limiting the indication to add bevacizumab in patients affected by metastatic, unresectable uterine leiomyosarcoma. The current evidence does not justify the use of bevacizumab into clinical practice. Further randomized studies testing the role of bevacizumab are warranted.
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Genetic alterations crossing the borders of distinct hematopoetic lineages and solid tumors: Diagnostic challenges in the era of high-throughput sequencing in hemato-oncology
Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Evgenii Shumilov, Johanna Flach, Thomas Pabst, Martin Fiedler, Anne Angelillo-Scherrer, Lorenz Trümper, Raphael Joncourt, Alexander Kohlmann, Ulrike Bacher
Owing to the introduction of next-generation sequencing (NGS) new challenges for diagnostic algorithms and the interpretation of the results for therapeutic decision making in hemato-oncology have arisen. Recurrent somatic mutations crossing the borders between different hematological entities and solid neoplasms have been detected. In analogy to mutant TP53, the same mutation type may occur in myeloid, B- or T-lymphatic malignancies or solid neoplasms. At the same time, a certain mutation can show different prognostic outcomes in different entities and co-existence of certain mutations may change the prognostic relevance. These insights may spark the investigation of targeted therapies with the same substances across different disease entities. This review article summarizes mutations that can emerge in different hematologic and solid malignancies and summarizes other obstacles in the era of modern molecular diagnostics, such as the phenomenon of "clonal hematopoiesis of indeterminate potential" being difficult to interpret in the individual patient.
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Prognostic and Predictive Factors in Patients with Brain Metastases from Solid Tumors: A Review of Published Nomograms
Publication date: Available online 29 March 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Carsten Nieder, Minesh P. Mehta, Hans Geinitz, Anca L. Grosu
ObjectiveTo review published nomograms that predict endpoints such as overall survival (OS) or risk of intracranial relapse in patients with brain metastases from solid tumors.MethodsThe methods and results of nomogram studies identified by a systematic search were extracted and compared, stratified by endpoint predicted by the respective nomograms. In particular, validation strategies (external/internal), concordance indices (cut-off 0.75) and comparisons to older models were analyzed.ResultsSix publications reported on prediction of OS. Most of these analyses focused on one particular primary tumor site, e.g., breast cancer or hepatocellular carcinoma, while the largest study included different primary tumor sites. The median number of patients was 244. Three of six studies included external validation cohorts. With few exceptions, concordance indices <0.75 were reported. In all studies reporting this endpoint, the nomogram outperformed older prognostic scores. Two nomograms focused on development of new brain metastases after radiosurgery (one externally validated), one on survival free from salvage whole brain radiotherapy (WBRT) after radiosurgery, and one on neurologic and non-neurologic death in patients receiving radiosurgery after WBRT failure. All concordance indices of these 4 nomograms were <0.70.ConclusionTaking into account concordance indices and comparisons to older prognostic models, the most promising, externally validated nomograms are the breast cancer and the non-small cell lung cancer nomogram predicting OS, and the distant brain failure after radiosurgery nomogram. Additional validation studies as well as continuous monitoring of the models' performance appear necessary to ensure their clinical applicability in the present era of rapidly changing treatment paradigms.
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