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Engineered liver models to study human hepatotropic pathogens
Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.
The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.
For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.
Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.
Although 2D cultures offer ease of use and monitoring of infection, they often lack the complexity of the liver microenvironment and impact of different cell types on liver infections. A 3D radial-flow bioreactor (cylindrical matrix) was able to maintain and amplify human hepatoma cells (for example, Huh7 cells), by providing sufficient oxygen and nutrient supply, supporting productive HCV infection for months. Other 3D cultures of hepatoma cells using polyethylene glycol–based hydrogels, thermoreversible gelatin polymers, alginate, galactosylated cellulosic sponges, matrigel, and collagen have been developed and shown to be permissive to HCV or HBV infections. Although 3D coculture systems exhibit better hepatic function and differential gene expression profiles in comparison to 2D counterparts, they require a large quantity of cells and are a challenge to scale up. Recently, several liver-on-a-chip models have been created that mimic shear stress, blood flow, and the extracellular environment within a tissue, holding great potential for modeling liver-specific pathogens.
Humanized mouse models with ectopic human liver structures have been developed in which primary HHs are transplanted following liver injury. Chimeric mouse models including Alb-uPA/SCID (HHs transplanted into urokinase-type plasminogen activator-transgenic severe combined immunodeficient mice), FNRG/FRG (HHs transplanted into Fah[-/-], Rag2[-/-], and Il2rg[-/-] mice with or without a nonobese diabetic background), and TK-NOG (HHs transplanted into herpes simplex virus type-1 thymidine kinase mice) were validated for HCV, HBV, P. falciparum, and P. vivax infections. It is, however, laborious to create and maintain chimeric mouse models and monitor infection processes in them.
It is important to note that the selection of model system and the readout modality to monitor infection will vary based on the experimental question at hand. Tissue engineering has thus far made significant contributions to the knowledge of hepatotropic pathogens; a continued effort to develop better liver models is envisioned.
Gural et al. present a timely and outstanding review of the advances made in the engineering of human-relevant liver culture platforms for investigating the molecular mechanisms of infectious diseases (e.g., hepatitis B/C viruses and Plasmodium parasites that cause malaria) and developing better drugs or vaccines against such diseases. The authors cover a continuum of platforms with increasing physiological complexity, such as 2-D hepatocyte monocultures on collagen-coated plastic, 2-D cocultures of hepatocytes and nonparenchymal cells, (both randomly distributed and patterned into microdomains to optimize cell-cell contact), 3-D cultures/cocultures housed in biomaterial-based scaffolds, perfusion-based bioreactors to induce cell growth and phenotypic stability, and finally rodents with humanized livers. Cell sourcing considerations for building human-relevant platforms are discussed, including cancerous cell lines, primary human hepatocytes, and stem cell–derived hepatocytes (e.g., induced pluripotent stem cells).
From the discussions of various studies, it is clear that this field has benefitted tremendously from advances in tissue engineering, including microfabrication tools adapted from the semiconductor industry, to construct human liver platforms that last for several weeks in vitro, can be infected with hepatitis B/C virus and Plasmodium parasites with high efficiencies, and are very useful for high-throughput and high-content drug screening applications. The latest protocols in isolating and cryopreserving primary human hepatocytes and differentiating stem cells into hepatocyte-like cells with adult functions help reduce the reliance on abnormal or cancerous cell lines for building platforms with higher relevance to the clinic. Ultimately, continued advances in microfabricated human liver platforms can aid our understanding of liver infections and spur further drug/vaccine development.
Salman R. Khetani, PhD, is associate professor, department of bioengineering, University of Illinois at Chicago. He has no conflicts of interest.
Gural et al. present a timely and outstanding review of the advances made in the engineering of human-relevant liver culture platforms for investigating the molecular mechanisms of infectious diseases (e.g., hepatitis B/C viruses and Plasmodium parasites that cause malaria) and developing better drugs or vaccines against such diseases. The authors cover a continuum of platforms with increasing physiological complexity, such as 2-D hepatocyte monocultures on collagen-coated plastic, 2-D cocultures of hepatocytes and nonparenchymal cells, (both randomly distributed and patterned into microdomains to optimize cell-cell contact), 3-D cultures/cocultures housed in biomaterial-based scaffolds, perfusion-based bioreactors to induce cell growth and phenotypic stability, and finally rodents with humanized livers. Cell sourcing considerations for building human-relevant platforms are discussed, including cancerous cell lines, primary human hepatocytes, and stem cell–derived hepatocytes (e.g., induced pluripotent stem cells).
From the discussions of various studies, it is clear that this field has benefitted tremendously from advances in tissue engineering, including microfabrication tools adapted from the semiconductor industry, to construct human liver platforms that last for several weeks in vitro, can be infected with hepatitis B/C virus and Plasmodium parasites with high efficiencies, and are very useful for high-throughput and high-content drug screening applications. The latest protocols in isolating and cryopreserving primary human hepatocytes and differentiating stem cells into hepatocyte-like cells with adult functions help reduce the reliance on abnormal or cancerous cell lines for building platforms with higher relevance to the clinic. Ultimately, continued advances in microfabricated human liver platforms can aid our understanding of liver infections and spur further drug/vaccine development.
Salman R. Khetani, PhD, is associate professor, department of bioengineering, University of Illinois at Chicago. He has no conflicts of interest.
Gural et al. present a timely and outstanding review of the advances made in the engineering of human-relevant liver culture platforms for investigating the molecular mechanisms of infectious diseases (e.g., hepatitis B/C viruses and Plasmodium parasites that cause malaria) and developing better drugs or vaccines against such diseases. The authors cover a continuum of platforms with increasing physiological complexity, such as 2-D hepatocyte monocultures on collagen-coated plastic, 2-D cocultures of hepatocytes and nonparenchymal cells, (both randomly distributed and patterned into microdomains to optimize cell-cell contact), 3-D cultures/cocultures housed in biomaterial-based scaffolds, perfusion-based bioreactors to induce cell growth and phenotypic stability, and finally rodents with humanized livers. Cell sourcing considerations for building human-relevant platforms are discussed, including cancerous cell lines, primary human hepatocytes, and stem cell–derived hepatocytes (e.g., induced pluripotent stem cells).
From the discussions of various studies, it is clear that this field has benefitted tremendously from advances in tissue engineering, including microfabrication tools adapted from the semiconductor industry, to construct human liver platforms that last for several weeks in vitro, can be infected with hepatitis B/C virus and Plasmodium parasites with high efficiencies, and are very useful for high-throughput and high-content drug screening applications. The latest protocols in isolating and cryopreserving primary human hepatocytes and differentiating stem cells into hepatocyte-like cells with adult functions help reduce the reliance on abnormal or cancerous cell lines for building platforms with higher relevance to the clinic. Ultimately, continued advances in microfabricated human liver platforms can aid our understanding of liver infections and spur further drug/vaccine development.
Salman R. Khetani, PhD, is associate professor, department of bioengineering, University of Illinois at Chicago. He has no conflicts of interest.
Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.
The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.
For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.
Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.
Although 2D cultures offer ease of use and monitoring of infection, they often lack the complexity of the liver microenvironment and impact of different cell types on liver infections. A 3D radial-flow bioreactor (cylindrical matrix) was able to maintain and amplify human hepatoma cells (for example, Huh7 cells), by providing sufficient oxygen and nutrient supply, supporting productive HCV infection for months. Other 3D cultures of hepatoma cells using polyethylene glycol–based hydrogels, thermoreversible gelatin polymers, alginate, galactosylated cellulosic sponges, matrigel, and collagen have been developed and shown to be permissive to HCV or HBV infections. Although 3D coculture systems exhibit better hepatic function and differential gene expression profiles in comparison to 2D counterparts, they require a large quantity of cells and are a challenge to scale up. Recently, several liver-on-a-chip models have been created that mimic shear stress, blood flow, and the extracellular environment within a tissue, holding great potential for modeling liver-specific pathogens.
Humanized mouse models with ectopic human liver structures have been developed in which primary HHs are transplanted following liver injury. Chimeric mouse models including Alb-uPA/SCID (HHs transplanted into urokinase-type plasminogen activator-transgenic severe combined immunodeficient mice), FNRG/FRG (HHs transplanted into Fah[-/-], Rag2[-/-], and Il2rg[-/-] mice with or without a nonobese diabetic background), and TK-NOG (HHs transplanted into herpes simplex virus type-1 thymidine kinase mice) were validated for HCV, HBV, P. falciparum, and P. vivax infections. It is, however, laborious to create and maintain chimeric mouse models and monitor infection processes in them.
It is important to note that the selection of model system and the readout modality to monitor infection will vary based on the experimental question at hand. Tissue engineering has thus far made significant contributions to the knowledge of hepatotropic pathogens; a continued effort to develop better liver models is envisioned.
Recently, exciting clinical progress has been made in the study of hepatotropic pathogens in the context of liver-dependent infectious diseases. This is crucial for the development and validation of therapeutic interventions, such as drug and vaccine candidates that may act on the liver cells. The engineered models range from two-dimensional (2-D) cultures of primary human hepatocytes (HH) and stem cell–derived progeny to three-dimensional (3-D) organoid cultures and humanized rodent models. A review by Nil Gural and colleagues, published in Cellular and Molecular Gastroenterology and Hepatology, described these unique models. Furthermore, the progress made in combining individual approaches and pairing the most appropriate model system and readout modality was discussed.
The major human hepatotropic pathogens include hepatitis C virus (HCV), hepatitis B virus (HBV), and the protozoan parasites Plasmodium falciparum and P. vivax. While HBV and HCV can cause chronic liver diseases such as cirrhosis and hepatocellular carcinoma, Plasmodium parasites cause malaria. The use of cancer cell lines and animal models to study host-pathogen interactions is limited by uncontrolled proliferation, abnormal liver-specific functions, and stringent host dependency of the hepatotropic pathogens. HHs are thus the only ideal system to study these pathogens, however, maintaining these cells ex vivo is challenging.
For instance, 2D monolayers of human hepatoma-derived cell lines (such as HepG2-A16 and HepaRG) are easier to maintain, to amplify for scaling up, and to use for drug screening, thus representing a renewable alternative to primary hepatocytes. These model systems have been useful to study short-term infections of human Plasmodium parasites (P. vivax and P. falciparum); other hepatotropic pathogens such as Ebola, Lassa, human cytomegalovirus, and dengue viruses; and to generate virion stocks (HCV, HBV). For long-term scientific analyses and cultures, as well as clinical isolates of pathogens that do not infect hepatoma cells, immortalized cell lines have been engineered to differentiate and maintain HH functions for a longer duration. Additionally, cocultivation of primary hepatocytes with nonparenchymal cells or hepatocytes with mouse fibroblasts preserves hepatocyte phenotype. The latter is a self-assembling coculture system that could potentially maintain an infection for over 30 days and be used for testing anti-HBV drugs. A micropatterned coculture system, in which hepatocytes are positioned in “islands” via photolithographic patterning of collagen, surrounded by mouse embryonic fibroblasts, can maintain hepatocyte phenotypes for 4-6 weeks, and remain permissive to P. falciparum, P. vivax, HBV, and HCV infections. Furthermore, micropatterned coculture systems support full developmental liver stages of both P. falciparum and P. vivax, with the release of merozoites from hepatocytes and their subsequent infection of overlaid human red blood cells.
Alternatively, embryonic stem cells and induced pluripotent stem cells of human origin can be differentiated into hepatocytelike cells that enable investigation of host genetics within the context of host-pathogen interactions, and can also be used for target identification for drug development. However, stem cell cultures require significant culture expertise and may not represent a fully differentiated adult hepatocyte phenotype.
Although 2D cultures offer ease of use and monitoring of infection, they often lack the complexity of the liver microenvironment and impact of different cell types on liver infections. A 3D radial-flow bioreactor (cylindrical matrix) was able to maintain and amplify human hepatoma cells (for example, Huh7 cells), by providing sufficient oxygen and nutrient supply, supporting productive HCV infection for months. Other 3D cultures of hepatoma cells using polyethylene glycol–based hydrogels, thermoreversible gelatin polymers, alginate, galactosylated cellulosic sponges, matrigel, and collagen have been developed and shown to be permissive to HCV or HBV infections. Although 3D coculture systems exhibit better hepatic function and differential gene expression profiles in comparison to 2D counterparts, they require a large quantity of cells and are a challenge to scale up. Recently, several liver-on-a-chip models have been created that mimic shear stress, blood flow, and the extracellular environment within a tissue, holding great potential for modeling liver-specific pathogens.
Humanized mouse models with ectopic human liver structures have been developed in which primary HHs are transplanted following liver injury. Chimeric mouse models including Alb-uPA/SCID (HHs transplanted into urokinase-type plasminogen activator-transgenic severe combined immunodeficient mice), FNRG/FRG (HHs transplanted into Fah[-/-], Rag2[-/-], and Il2rg[-/-] mice with or without a nonobese diabetic background), and TK-NOG (HHs transplanted into herpes simplex virus type-1 thymidine kinase mice) were validated for HCV, HBV, P. falciparum, and P. vivax infections. It is, however, laborious to create and maintain chimeric mouse models and monitor infection processes in them.
It is important to note that the selection of model system and the readout modality to monitor infection will vary based on the experimental question at hand. Tissue engineering has thus far made significant contributions to the knowledge of hepatotropic pathogens; a continued effort to develop better liver models is envisioned.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Objective response rate correlates poorly with overall survival in checkpoint-inhibitor trials
Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.
Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.
Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.
The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.
Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.
Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.
A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.
The authors reported no conflicts of interest.
SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.
Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.
Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.
Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.
The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.
Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.
Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.
A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.
The authors reported no conflicts of interest.
SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.
Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.
Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.
Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.
The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.
Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.
Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.
A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.
The authors reported no conflicts of interest.
SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.
FROM JAMA ONCOLOGY
Key clinical point: Immune checkpoint inhibitors activate anti-tumor T-cells to detect and destroy tumor cells and have become the standard of care for many patients with advanced solid cancers. The most appropriate primary endpoint in phase 2 trials of checkpoint inhibitors remains uncertain.
Major finding: In this systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers, objective response rate correlated poorly with overall survival, but 6-month progression-free survival was a better predictor of 12-month overall survival.
Study details: Trials listed in electronic databases from 2000 to 2017 (PREMEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials).
Disclosures: None reported.
Source: Ritchie G et al. JAMA Oncol. 2018 Feb 22. doi: 10.1001/jamaoncol.2017.5236.
NF-kappaB pathway could help solve resistance problem in mantle cell lymphoma
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
FROM CELL DEATH & DISEASE
Unscheduled visits for pain after hernia surgery common, costly
And although these calls and visits are costly in health care resources, many patients do not receive an actionable diagnosis, according to a study published in The American Journal of Surgery.
Colin G. DeLong, MD, and his colleagues reviewed health records of patients who underwent an open procedure for complex ventral hernia repair (cVHR) at Penn State Milton S. Hershey Medical Center in Hershey, Penn., between January 2013 and August 2015 using the American College of Surgeons National Surgery Quality Improvement Project (NSQIP) data available at the institution. They identified a cohort of 177 patients, 79% of whom were reviewed for pain issues at 1 year.
The study focused on postoperative pain during the first year following open cVHR. The investigators looked at how patients registered postoperative discomfort, risk factors that predicted greater utilization of the health system for pain-related complaints, and how often complaints of chronic pain resulted in an actionable diagnosis.
All postop encounters in the year after surgery were documented, including the sequence of events in response to pain complaints. In addition, the investigators recorded “instances in which a diagnosis resulted from such actions and whether the diagnosis was actionable, meaning it led to a specific intervention that was expected to alleviate the pain.”
Of the 177 patients, 91 patients made an unsolicited call, clinic visit, or ED visit for pain issues. For 38 patients in this group, action was taken (additional prescription, imaging ordered, ED workup recommended or undertaken). For the other 53, no action was taken. From each group, some cases resolved because of further intervention, and some cases resolved without further action. Mesh use and preoperative pain scores were predictors of postop pain, but not age, ethnicity, sex, or other comorbidities. But 38 (21%) patients continued to have pain that was not resolved at 1 year, 32 of which had no actionable diagnosis.
The study was retrospective and limited by inclusion of visits and calls only to the surgical services and not to other medical services or physicians. Pain complaints were subjective and levels of severity were not recorded.
The investigators concluded that estimates of the number of patients who have chronic pain after cVHR do not capture the level of health care resource utilization for this problem. Patients experiencing postop pain make unscheduled calls or visits to the clinic or ED, and many do so repeatedly without receiving an actionable diagnosis. “A cost analysis specific to treating postoperative pain for 1 year would provide a better understanding of the magnitude of the problem. Subjective complaints of pain in the year following cVHR are frequent and represent a hidden driver of resource utilization which must be better understood to achieve optimal, cost effective care.”
The authors declared no conflicts of interest.
SOURCE: DeLong CG et al. Am J Surg. 2018. doi: 10.1016/j.amjsurg.2018.01.030.
And although these calls and visits are costly in health care resources, many patients do not receive an actionable diagnosis, according to a study published in The American Journal of Surgery.
Colin G. DeLong, MD, and his colleagues reviewed health records of patients who underwent an open procedure for complex ventral hernia repair (cVHR) at Penn State Milton S. Hershey Medical Center in Hershey, Penn., between January 2013 and August 2015 using the American College of Surgeons National Surgery Quality Improvement Project (NSQIP) data available at the institution. They identified a cohort of 177 patients, 79% of whom were reviewed for pain issues at 1 year.
The study focused on postoperative pain during the first year following open cVHR. The investigators looked at how patients registered postoperative discomfort, risk factors that predicted greater utilization of the health system for pain-related complaints, and how often complaints of chronic pain resulted in an actionable diagnosis.
All postop encounters in the year after surgery were documented, including the sequence of events in response to pain complaints. In addition, the investigators recorded “instances in which a diagnosis resulted from such actions and whether the diagnosis was actionable, meaning it led to a specific intervention that was expected to alleviate the pain.”
Of the 177 patients, 91 patients made an unsolicited call, clinic visit, or ED visit for pain issues. For 38 patients in this group, action was taken (additional prescription, imaging ordered, ED workup recommended or undertaken). For the other 53, no action was taken. From each group, some cases resolved because of further intervention, and some cases resolved without further action. Mesh use and preoperative pain scores were predictors of postop pain, but not age, ethnicity, sex, or other comorbidities. But 38 (21%) patients continued to have pain that was not resolved at 1 year, 32 of which had no actionable diagnosis.
The study was retrospective and limited by inclusion of visits and calls only to the surgical services and not to other medical services or physicians. Pain complaints were subjective and levels of severity were not recorded.
The investigators concluded that estimates of the number of patients who have chronic pain after cVHR do not capture the level of health care resource utilization for this problem. Patients experiencing postop pain make unscheduled calls or visits to the clinic or ED, and many do so repeatedly without receiving an actionable diagnosis. “A cost analysis specific to treating postoperative pain for 1 year would provide a better understanding of the magnitude of the problem. Subjective complaints of pain in the year following cVHR are frequent and represent a hidden driver of resource utilization which must be better understood to achieve optimal, cost effective care.”
The authors declared no conflicts of interest.
SOURCE: DeLong CG et al. Am J Surg. 2018. doi: 10.1016/j.amjsurg.2018.01.030.
And although these calls and visits are costly in health care resources, many patients do not receive an actionable diagnosis, according to a study published in The American Journal of Surgery.
Colin G. DeLong, MD, and his colleagues reviewed health records of patients who underwent an open procedure for complex ventral hernia repair (cVHR) at Penn State Milton S. Hershey Medical Center in Hershey, Penn., between January 2013 and August 2015 using the American College of Surgeons National Surgery Quality Improvement Project (NSQIP) data available at the institution. They identified a cohort of 177 patients, 79% of whom were reviewed for pain issues at 1 year.
The study focused on postoperative pain during the first year following open cVHR. The investigators looked at how patients registered postoperative discomfort, risk factors that predicted greater utilization of the health system for pain-related complaints, and how often complaints of chronic pain resulted in an actionable diagnosis.
All postop encounters in the year after surgery were documented, including the sequence of events in response to pain complaints. In addition, the investigators recorded “instances in which a diagnosis resulted from such actions and whether the diagnosis was actionable, meaning it led to a specific intervention that was expected to alleviate the pain.”
Of the 177 patients, 91 patients made an unsolicited call, clinic visit, or ED visit for pain issues. For 38 patients in this group, action was taken (additional prescription, imaging ordered, ED workup recommended or undertaken). For the other 53, no action was taken. From each group, some cases resolved because of further intervention, and some cases resolved without further action. Mesh use and preoperative pain scores were predictors of postop pain, but not age, ethnicity, sex, or other comorbidities. But 38 (21%) patients continued to have pain that was not resolved at 1 year, 32 of which had no actionable diagnosis.
The study was retrospective and limited by inclusion of visits and calls only to the surgical services and not to other medical services or physicians. Pain complaints were subjective and levels of severity were not recorded.
The investigators concluded that estimates of the number of patients who have chronic pain after cVHR do not capture the level of health care resource utilization for this problem. Patients experiencing postop pain make unscheduled calls or visits to the clinic or ED, and many do so repeatedly without receiving an actionable diagnosis. “A cost analysis specific to treating postoperative pain for 1 year would provide a better understanding of the magnitude of the problem. Subjective complaints of pain in the year following cVHR are frequent and represent a hidden driver of resource utilization which must be better understood to achieve optimal, cost effective care.”
The authors declared no conflicts of interest.
SOURCE: DeLong CG et al. Am J Surg. 2018. doi: 10.1016/j.amjsurg.2018.01.030.
FROM THE AMERICAN JOURNAL OF SURGERY
Key clinical point: Chronic pain has a significant effect on resource utilization following complex ventral hernia repair.
Major finding: Of patients who made unscheduled calls or visits to the clinic or ED for postop pain, 21% did not receive an actionable diagnosis.
Study details: Records from the ACS NSQIP of 177 patients undergoing cVHR were reviewed for postop pain visits and follow-up.
Disclosures: The authors declared no conflicts of interest.
Source: DeLong CG et al. Am J Surg. 2018. doi: 10.1016/j.amjsurg.2018.01.030.
National Early Warning Score discriminates deterioration of inpatients with liver disease
, within 24 hours in hospitalized patients, according to a study published in the journal Clinical Gastroenterology and Hepatology.
Although existing predictive models estimate medium- and long-term prognosis in patients with liver disease, none are validated for short-term outcomes in inpatient settings. Despite the potential concern that patients with liver disease present with chronic physiological derangements affecting National Early Warning Score (NEWS) parameters, the score accurately discriminated patients at risk of death, admission to the ICU, or cardiac arrest within a 24-hour period for a range of liver-related diagnoses achieving an area under receiver operating characteristics (AUROC) curve of 0.894 (95% confidence intervals, 0.887-0.902), 0.857 (95% CI, 0.847-0.868), and 0.722 (95% CI, 0.685-0.759), respectively.
NEWS was launched in 2012 to reduce variations among existing early warning scores by the Royal College of Physicians for use in all adults except pregnant women. Theresa J. Hydes MD, PhD, and her colleagues at the department of gastroenterology & hepatology, Portsmouth (England) Hospitals NHS Trust, sought to validate NEWS in 35,585 unselected medical patients.
The NEWS allocates weighted points, based on derangement of vital signs from defined normal ranges including pulse, respiratory rate, systolic blood pressure, an alert-verbal-painful-unresponsive scale, temperature, peripheral oxygen saturations, and use of supplemental oxygen. The summation of allocated points to directs changes in the level of care, for example, more frequent monitoring, involving senior staff, or calling a rapid response team.
The study was performed in a large, acute care hospital in southern England and analyzed a database of electronically captured vital signs recorded in real time from completed consecutive admissions of patients aged 16 years or older, during 2010-2014. International Classification of Diseases-10 codes were used to categorize patients for any finished consultant episode. The categories included patients with primary diagnosis of liver disease, those with nonprimary liver diagnosis (comorbidity), and patients not allocated any liver disease codes (controls). The NEWS performance was examined according to whether liver disease was acute or chronic, alcohol induced, or associated with portal hypertension, with four clinical subgroups: acute alcohol-induced liver injury, other acute injury, chronic liver disease without cirrhosis, or cirrhosis. The final dataset comprised 722 patients (1,112 episodes) with a primary liver diagnosis, and 2,339 patients (3,658 episodes) with a nonprimary liver diagnosis.
The primary study endpoint was any of the following events occurring within 24 hours of an observation set: in-hospital mortality, unanticipated ICU admission, or cardiac arrest. “The NEWS identified patients with primary, nonprimary, and no diagnoses of liver disease with AUROC values of 0.873 (95% CI, 0.860-0.886), 0.898 (95% CI, 0.891-0.905), and 0.879 (95% CI, 0.877-0.881), respectively. High AUROC values also were obtained for all clinical subgroups; the NEWS identified patients with alcohol-related liver disease with an AUROC value of 0.927 (95% CI, 0.912-0.941). The NEWS identified patients with liver diseases with higher AUROC values than [did] other early warning scoring systems,” according to Dr. Hydes and her colleagues.
“Because of its widespread use, the NEWS serves a ready-made, easy-to-use option for identifying patients with liver disease who require early assessment and intervention, without the need to modify parameters, weightings or escalation criteria,” wrote the authors.
The study was supported by VitalPAC, a collaborative development of the Learning Clinic and Portsmouth Hospitals NHS Trust. Dr. Schmidt, Dr. Aspinall, and Dr. Meredith are employed by PHT. Dr. Hydes had no conflicts of interest.
SOURCE: Hydes TJ et al. Clin Gastroenterol Hepatol. 2017 Dec 22. doi: 10.1016/j.cgh.2017.12.035.
, within 24 hours in hospitalized patients, according to a study published in the journal Clinical Gastroenterology and Hepatology.
Although existing predictive models estimate medium- and long-term prognosis in patients with liver disease, none are validated for short-term outcomes in inpatient settings. Despite the potential concern that patients with liver disease present with chronic physiological derangements affecting National Early Warning Score (NEWS) parameters, the score accurately discriminated patients at risk of death, admission to the ICU, or cardiac arrest within a 24-hour period for a range of liver-related diagnoses achieving an area under receiver operating characteristics (AUROC) curve of 0.894 (95% confidence intervals, 0.887-0.902), 0.857 (95% CI, 0.847-0.868), and 0.722 (95% CI, 0.685-0.759), respectively.
NEWS was launched in 2012 to reduce variations among existing early warning scores by the Royal College of Physicians for use in all adults except pregnant women. Theresa J. Hydes MD, PhD, and her colleagues at the department of gastroenterology & hepatology, Portsmouth (England) Hospitals NHS Trust, sought to validate NEWS in 35,585 unselected medical patients.
The NEWS allocates weighted points, based on derangement of vital signs from defined normal ranges including pulse, respiratory rate, systolic blood pressure, an alert-verbal-painful-unresponsive scale, temperature, peripheral oxygen saturations, and use of supplemental oxygen. The summation of allocated points to directs changes in the level of care, for example, more frequent monitoring, involving senior staff, or calling a rapid response team.
The study was performed in a large, acute care hospital in southern England and analyzed a database of electronically captured vital signs recorded in real time from completed consecutive admissions of patients aged 16 years or older, during 2010-2014. International Classification of Diseases-10 codes were used to categorize patients for any finished consultant episode. The categories included patients with primary diagnosis of liver disease, those with nonprimary liver diagnosis (comorbidity), and patients not allocated any liver disease codes (controls). The NEWS performance was examined according to whether liver disease was acute or chronic, alcohol induced, or associated with portal hypertension, with four clinical subgroups: acute alcohol-induced liver injury, other acute injury, chronic liver disease without cirrhosis, or cirrhosis. The final dataset comprised 722 patients (1,112 episodes) with a primary liver diagnosis, and 2,339 patients (3,658 episodes) with a nonprimary liver diagnosis.
The primary study endpoint was any of the following events occurring within 24 hours of an observation set: in-hospital mortality, unanticipated ICU admission, or cardiac arrest. “The NEWS identified patients with primary, nonprimary, and no diagnoses of liver disease with AUROC values of 0.873 (95% CI, 0.860-0.886), 0.898 (95% CI, 0.891-0.905), and 0.879 (95% CI, 0.877-0.881), respectively. High AUROC values also were obtained for all clinical subgroups; the NEWS identified patients with alcohol-related liver disease with an AUROC value of 0.927 (95% CI, 0.912-0.941). The NEWS identified patients with liver diseases with higher AUROC values than [did] other early warning scoring systems,” according to Dr. Hydes and her colleagues.
“Because of its widespread use, the NEWS serves a ready-made, easy-to-use option for identifying patients with liver disease who require early assessment and intervention, without the need to modify parameters, weightings or escalation criteria,” wrote the authors.
The study was supported by VitalPAC, a collaborative development of the Learning Clinic and Portsmouth Hospitals NHS Trust. Dr. Schmidt, Dr. Aspinall, and Dr. Meredith are employed by PHT. Dr. Hydes had no conflicts of interest.
SOURCE: Hydes TJ et al. Clin Gastroenterol Hepatol. 2017 Dec 22. doi: 10.1016/j.cgh.2017.12.035.
, within 24 hours in hospitalized patients, according to a study published in the journal Clinical Gastroenterology and Hepatology.
Although existing predictive models estimate medium- and long-term prognosis in patients with liver disease, none are validated for short-term outcomes in inpatient settings. Despite the potential concern that patients with liver disease present with chronic physiological derangements affecting National Early Warning Score (NEWS) parameters, the score accurately discriminated patients at risk of death, admission to the ICU, or cardiac arrest within a 24-hour period for a range of liver-related diagnoses achieving an area under receiver operating characteristics (AUROC) curve of 0.894 (95% confidence intervals, 0.887-0.902), 0.857 (95% CI, 0.847-0.868), and 0.722 (95% CI, 0.685-0.759), respectively.
NEWS was launched in 2012 to reduce variations among existing early warning scores by the Royal College of Physicians for use in all adults except pregnant women. Theresa J. Hydes MD, PhD, and her colleagues at the department of gastroenterology & hepatology, Portsmouth (England) Hospitals NHS Trust, sought to validate NEWS in 35,585 unselected medical patients.
The NEWS allocates weighted points, based on derangement of vital signs from defined normal ranges including pulse, respiratory rate, systolic blood pressure, an alert-verbal-painful-unresponsive scale, temperature, peripheral oxygen saturations, and use of supplemental oxygen. The summation of allocated points to directs changes in the level of care, for example, more frequent monitoring, involving senior staff, or calling a rapid response team.
The study was performed in a large, acute care hospital in southern England and analyzed a database of electronically captured vital signs recorded in real time from completed consecutive admissions of patients aged 16 years or older, during 2010-2014. International Classification of Diseases-10 codes were used to categorize patients for any finished consultant episode. The categories included patients with primary diagnosis of liver disease, those with nonprimary liver diagnosis (comorbidity), and patients not allocated any liver disease codes (controls). The NEWS performance was examined according to whether liver disease was acute or chronic, alcohol induced, or associated with portal hypertension, with four clinical subgroups: acute alcohol-induced liver injury, other acute injury, chronic liver disease without cirrhosis, or cirrhosis. The final dataset comprised 722 patients (1,112 episodes) with a primary liver diagnosis, and 2,339 patients (3,658 episodes) with a nonprimary liver diagnosis.
The primary study endpoint was any of the following events occurring within 24 hours of an observation set: in-hospital mortality, unanticipated ICU admission, or cardiac arrest. “The NEWS identified patients with primary, nonprimary, and no diagnoses of liver disease with AUROC values of 0.873 (95% CI, 0.860-0.886), 0.898 (95% CI, 0.891-0.905), and 0.879 (95% CI, 0.877-0.881), respectively. High AUROC values also were obtained for all clinical subgroups; the NEWS identified patients with alcohol-related liver disease with an AUROC value of 0.927 (95% CI, 0.912-0.941). The NEWS identified patients with liver diseases with higher AUROC values than [did] other early warning scoring systems,” according to Dr. Hydes and her colleagues.
“Because of its widespread use, the NEWS serves a ready-made, easy-to-use option for identifying patients with liver disease who require early assessment and intervention, without the need to modify parameters, weightings or escalation criteria,” wrote the authors.
The study was supported by VitalPAC, a collaborative development of the Learning Clinic and Portsmouth Hospitals NHS Trust. Dr. Schmidt, Dr. Aspinall, and Dr. Meredith are employed by PHT. Dr. Hydes had no conflicts of interest.
SOURCE: Hydes TJ et al. Clin Gastroenterol Hepatol. 2017 Dec 22. doi: 10.1016/j.cgh.2017.12.035.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The performance of the National Early Warning Score, used to identify deteriorating adult hospital inpatients with acute and chronic liver diseases within 24 hours of admission, was assessed.
Major finding: NEWS accurately discriminates risk of death, ICU admission, or cardiac arrest within 24 hours in patients with liver-related diagnoses.
Study details: A database of electronically captured vital signs recorded in real-time from completed consecutive admissions (episodes) of patients aged at least 16 years between Jan. 1, 2010, and Oct. 31, 2014. Nurses recorded data at the bedside using electronic devices running VitalPAC software.
Disclosures: The study was supported by VitalPAC, a collaborative development of the Learning Clinic and Portsmouth Hospitals NHS Trust (PHT). Dr. Schmidt, Dr. Aspinall, and Dr. Meredith are employed by PHT. Dr. Hydes had no conflicts of interest.
Source: Hydes TJ et al. Clin Gastroenterol Hepatol. 2017 Dec 22. doi: 10.1016/j.cgh.2017.12.035
PAM50-based score identifies low-risk subset with node-positive early-stage breast cancer
The PAM50-based risk of recurrence (ROR) score enabled selection of a subset of patients with estrogen receptor (ER)–positive early-stage breast cancer with node-positive or node-negative disease with an estimated 10-year distant recurrence (DR) absolute risk of less than 5%, investigators reported.
This subset of patients with one to three positive lymph nodes presented a sufficiently low risk of disease recurrence and could safely avoid chemotherapy, reported Anne-Vibeke Laenkholm, MD, and her associates. The report was published in the Journal of Clinical Oncology.
The PAM50-based ROR score (Prosigna Score; Nanostring Technologies, Seattle) is a comparative gene expression profile of the tumor, relative to each of the four PAM50 molecular profiles (luminal A, luminal B, basal, and HER2 enriched) to determine the degree of similarity. The Prosigna assay currently has Food and Drug Administration clearance for prognostic use.
Postmenopausal women diagnosed with ER-positive/HER2-negative early-stage breast cancer in Denmark between 2000 and 2003, and who received adjuvant treatment with tamoxifen or an aromatase inhibitor without chemotherapy were eligible for this cohort study.
The primary endpoint was time to DR, defined as the interval from breast cancer surgery until DR or death as a result of breast cancer. Secondary endpoints included overall survival and time to any recurrence. “The median age of patients was 63 years (range, 50-89 years); 45.5% were node negative, and 54.5% had one to three positive nodes. Tumor characteristics including nodal status, tumor size, malignancy grade, and lymphovascular invasion were all associated with DR, whereas treatment adherence was not,” wrote Dr. Laenkholm of the department of surgical pathology, Zealand University Hospital, Denmark, and her colleagues.
“With a median follow-up of approximately 9 years, 26% of the patients with node-positive disease were categorized as having a low ROR score corresponding to a DR of 3.5% at 10 years compared with those with an intermediate ROR score with a DR of 11.5% and those with a high ROR score corresponding to a DR risk of 22%. In the node-negative group, those with a low ROR score had a 10-year DR risk of 5% and those with an intermediate ROR score had a 7.3% 10-year DR risk, compared with a DR of 17.8% in those with a high ROR score,” Dr. Laenkholm and her associates reported.
The data are entirely prognostic and do not address whether chemotherapy might offer some benefit in a node-positive population (i.e., one to three nodes), or whether adjuvant chemotherapy–associated adverse effects may offset the added benefit, if any, the investigators said.
Nonetheless, genomic assay–based scoring tools are an important aid in clinical decision making readily available to the physician at the patient’s bedside, they said.
Nanostring Technologies funded the study. Laboratory work flow was executed at the department of surgical pathology, Zealand University Hospital. Several authors reported ties with Roche and other pharmaceutical companies.
SOURCE: Laenkholm et al. J Clin Oncol. 2018 Jan 25. doi: 10.1200/JCO.2017.74.6586.
The study by Laenkholm et al. provides encouraging data for the clinical utility of molecular assays to aid decision making for node-positive disease.
The investigators were able to select a subset of patients with node-positive disease with an estimated 10-year distant recurrence risk of less than or equal to 5%, based on the PAM50 risk of recurrence score. It could be argued that the data do not address the issue of whether chemotherapy would offer some benefit (predictive) in a node-positive population; however, a counterargument is that whatever small added benefit may be derived from adjuvant chemotherapy would be offset by adverse effects, resulting in a net gain of zero. The collective data from evaluation of other assays in this population suggest that patients with ER-positive disease, one to three positive nodes, and a low recurrence score can safely avoid adjuvant chemotherapy and receive endocrine therapy alone. This supports the current NCCN guidelines, which indicate the recurrence score assay can be considered in patients with one to three positive nodes. The more definitive answer on whether adjuvant chemotherapy adds benefit to endocrine therapy will be determined from the RxPONDER study, in which patients with ER+ disease, one to three positive nodes, and a recurrence score less than or equal to 25 will be randomly assigned to chemotherapy or not.
Ricardo L. B. Costa, MD, MS, is with the H. Lee Moffitt Cancer Center, Tampa. William J. Gradishar, MD, is with Northwestern University, Chicago. Dr. Costa disclosed ties with Bristol-Myers Squibb. Dr. Gradishar reported having no relevant financial disclosures. Their comments were adapted from an editorial (J Clin Oncol. 2018 Jan 25. doi: 10.1200/JCO.2017.76.9802).
The study by Laenkholm et al. provides encouraging data for the clinical utility of molecular assays to aid decision making for node-positive disease.
The investigators were able to select a subset of patients with node-positive disease with an estimated 10-year distant recurrence risk of less than or equal to 5%, based on the PAM50 risk of recurrence score. It could be argued that the data do not address the issue of whether chemotherapy would offer some benefit (predictive) in a node-positive population; however, a counterargument is that whatever small added benefit may be derived from adjuvant chemotherapy would be offset by adverse effects, resulting in a net gain of zero. The collective data from evaluation of other assays in this population suggest that patients with ER-positive disease, one to three positive nodes, and a low recurrence score can safely avoid adjuvant chemotherapy and receive endocrine therapy alone. This supports the current NCCN guidelines, which indicate the recurrence score assay can be considered in patients with one to three positive nodes. The more definitive answer on whether adjuvant chemotherapy adds benefit to endocrine therapy will be determined from the RxPONDER study, in which patients with ER+ disease, one to three positive nodes, and a recurrence score less than or equal to 25 will be randomly assigned to chemotherapy or not.
Ricardo L. B. Costa, MD, MS, is with the H. Lee Moffitt Cancer Center, Tampa. William J. Gradishar, MD, is with Northwestern University, Chicago. Dr. Costa disclosed ties with Bristol-Myers Squibb. Dr. Gradishar reported having no relevant financial disclosures. Their comments were adapted from an editorial (J Clin Oncol. 2018 Jan 25. doi: 10.1200/JCO.2017.76.9802).
The study by Laenkholm et al. provides encouraging data for the clinical utility of molecular assays to aid decision making for node-positive disease.
The investigators were able to select a subset of patients with node-positive disease with an estimated 10-year distant recurrence risk of less than or equal to 5%, based on the PAM50 risk of recurrence score. It could be argued that the data do not address the issue of whether chemotherapy would offer some benefit (predictive) in a node-positive population; however, a counterargument is that whatever small added benefit may be derived from adjuvant chemotherapy would be offset by adverse effects, resulting in a net gain of zero. The collective data from evaluation of other assays in this population suggest that patients with ER-positive disease, one to three positive nodes, and a low recurrence score can safely avoid adjuvant chemotherapy and receive endocrine therapy alone. This supports the current NCCN guidelines, which indicate the recurrence score assay can be considered in patients with one to three positive nodes. The more definitive answer on whether adjuvant chemotherapy adds benefit to endocrine therapy will be determined from the RxPONDER study, in which patients with ER+ disease, one to three positive nodes, and a recurrence score less than or equal to 25 will be randomly assigned to chemotherapy or not.
Ricardo L. B. Costa, MD, MS, is with the H. Lee Moffitt Cancer Center, Tampa. William J. Gradishar, MD, is with Northwestern University, Chicago. Dr. Costa disclosed ties with Bristol-Myers Squibb. Dr. Gradishar reported having no relevant financial disclosures. Their comments were adapted from an editorial (J Clin Oncol. 2018 Jan 25. doi: 10.1200/JCO.2017.76.9802).
The PAM50-based risk of recurrence (ROR) score enabled selection of a subset of patients with estrogen receptor (ER)–positive early-stage breast cancer with node-positive or node-negative disease with an estimated 10-year distant recurrence (DR) absolute risk of less than 5%, investigators reported.
This subset of patients with one to three positive lymph nodes presented a sufficiently low risk of disease recurrence and could safely avoid chemotherapy, reported Anne-Vibeke Laenkholm, MD, and her associates. The report was published in the Journal of Clinical Oncology.
The PAM50-based ROR score (Prosigna Score; Nanostring Technologies, Seattle) is a comparative gene expression profile of the tumor, relative to each of the four PAM50 molecular profiles (luminal A, luminal B, basal, and HER2 enriched) to determine the degree of similarity. The Prosigna assay currently has Food and Drug Administration clearance for prognostic use.
Postmenopausal women diagnosed with ER-positive/HER2-negative early-stage breast cancer in Denmark between 2000 and 2003, and who received adjuvant treatment with tamoxifen or an aromatase inhibitor without chemotherapy were eligible for this cohort study.
The primary endpoint was time to DR, defined as the interval from breast cancer surgery until DR or death as a result of breast cancer. Secondary endpoints included overall survival and time to any recurrence. “The median age of patients was 63 years (range, 50-89 years); 45.5% were node negative, and 54.5% had one to three positive nodes. Tumor characteristics including nodal status, tumor size, malignancy grade, and lymphovascular invasion were all associated with DR, whereas treatment adherence was not,” wrote Dr. Laenkholm of the department of surgical pathology, Zealand University Hospital, Denmark, and her colleagues.
“With a median follow-up of approximately 9 years, 26% of the patients with node-positive disease were categorized as having a low ROR score corresponding to a DR of 3.5% at 10 years compared with those with an intermediate ROR score with a DR of 11.5% and those with a high ROR score corresponding to a DR risk of 22%. In the node-negative group, those with a low ROR score had a 10-year DR risk of 5% and those with an intermediate ROR score had a 7.3% 10-year DR risk, compared with a DR of 17.8% in those with a high ROR score,” Dr. Laenkholm and her associates reported.
The data are entirely prognostic and do not address whether chemotherapy might offer some benefit in a node-positive population (i.e., one to three nodes), or whether adjuvant chemotherapy–associated adverse effects may offset the added benefit, if any, the investigators said.
Nonetheless, genomic assay–based scoring tools are an important aid in clinical decision making readily available to the physician at the patient’s bedside, they said.
Nanostring Technologies funded the study. Laboratory work flow was executed at the department of surgical pathology, Zealand University Hospital. Several authors reported ties with Roche and other pharmaceutical companies.
SOURCE: Laenkholm et al. J Clin Oncol. 2018 Jan 25. doi: 10.1200/JCO.2017.74.6586.
The PAM50-based risk of recurrence (ROR) score enabled selection of a subset of patients with estrogen receptor (ER)–positive early-stage breast cancer with node-positive or node-negative disease with an estimated 10-year distant recurrence (DR) absolute risk of less than 5%, investigators reported.
This subset of patients with one to three positive lymph nodes presented a sufficiently low risk of disease recurrence and could safely avoid chemotherapy, reported Anne-Vibeke Laenkholm, MD, and her associates. The report was published in the Journal of Clinical Oncology.
The PAM50-based ROR score (Prosigna Score; Nanostring Technologies, Seattle) is a comparative gene expression profile of the tumor, relative to each of the four PAM50 molecular profiles (luminal A, luminal B, basal, and HER2 enriched) to determine the degree of similarity. The Prosigna assay currently has Food and Drug Administration clearance for prognostic use.
Postmenopausal women diagnosed with ER-positive/HER2-negative early-stage breast cancer in Denmark between 2000 and 2003, and who received adjuvant treatment with tamoxifen or an aromatase inhibitor without chemotherapy were eligible for this cohort study.
The primary endpoint was time to DR, defined as the interval from breast cancer surgery until DR or death as a result of breast cancer. Secondary endpoints included overall survival and time to any recurrence. “The median age of patients was 63 years (range, 50-89 years); 45.5% were node negative, and 54.5% had one to three positive nodes. Tumor characteristics including nodal status, tumor size, malignancy grade, and lymphovascular invasion were all associated with DR, whereas treatment adherence was not,” wrote Dr. Laenkholm of the department of surgical pathology, Zealand University Hospital, Denmark, and her colleagues.
“With a median follow-up of approximately 9 years, 26% of the patients with node-positive disease were categorized as having a low ROR score corresponding to a DR of 3.5% at 10 years compared with those with an intermediate ROR score with a DR of 11.5% and those with a high ROR score corresponding to a DR risk of 22%. In the node-negative group, those with a low ROR score had a 10-year DR risk of 5% and those with an intermediate ROR score had a 7.3% 10-year DR risk, compared with a DR of 17.8% in those with a high ROR score,” Dr. Laenkholm and her associates reported.
The data are entirely prognostic and do not address whether chemotherapy might offer some benefit in a node-positive population (i.e., one to three nodes), or whether adjuvant chemotherapy–associated adverse effects may offset the added benefit, if any, the investigators said.
Nonetheless, genomic assay–based scoring tools are an important aid in clinical decision making readily available to the physician at the patient’s bedside, they said.
Nanostring Technologies funded the study. Laboratory work flow was executed at the department of surgical pathology, Zealand University Hospital. Several authors reported ties with Roche and other pharmaceutical companies.
SOURCE: Laenkholm et al. J Clin Oncol. 2018 Jan 25. doi: 10.1200/JCO.2017.74.6586.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: The score enabled selection of a subset of patients with node-positive or node-negative disease with an estimated 10-year DR absolute risk of less than 5%.
Major finding: About 37% of patients with a single positive lymph node and 15% of patients with two positive nodes were identified as low risk by Prosigna, with very favorable outcomes when treated with adjuvant endocrine therapy alone.
Study details: Danish Breast Cancer Cooperative Group database including postmenopausal patients in Denmark diagnosed with ER-positive invasive breast cancer from 2000 through 2003 and treated with endocrine therapy for 5 years.
Disclosures: Nanostring Technologies funded the study. Laboratory work flow was executed at the department of surgical pathology, Zealand University Hospital. Several authors reported ties with Roche and other pharmaceutical companies.
Source: Laenkholm et al. J Clin Oncol. 2018 Jan 25. doi: 10.1200/JCO.2017.74.6586.
CLL Index proves accurate in predicting survival, time to treat
An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).
But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.
Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”
The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.
The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.
They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).
The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.
Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.
The researchers reported having no financial disclosures.
An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).
But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.
Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”
The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.
The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.
They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).
The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.
Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.
The researchers reported having no financial disclosures.
An international prognostic index for patients with chronic lymphocytic leukemia (CLL), known as CLL-IPI, was predictive of time from diagnosis to first treatment (TTFT) and 5-year median overall survival in patients across different risk categories treated with chemoimmunotherapy, according to a systematic review and meta-analysis published in Blood (2018 Jan 18;131[3]:365-8).
But limited data were available for patients treated with targeted therapies that are likely to have a profound effect on overall survival; thereby restricting the use of CLL-IPI in current clinical practice.
Novel therapies such as ibrutinib, idelalisib, and venetoclax have changed the treatment landscape for CLL, Stefano Molica, MD, of Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy, and his colleagues wrote. “Because observation remains the standard of care for asymptomatic early-stage patients, the introduction of these agents does not impact the utility of the CLL-IPI for predicting time from diagnosis to first treatment, but it likely has a profound impact on the survival of patients of all risk categories once treatment is indicated.”
The CLL-IPI tool, first published in 2016 to predict clinical outcomes in CLL patients, combines five parameters: age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], immunoglobulin heavy chain–variable mutational status, and serum b2-microglobulin. The prognostic tool was validated across several studies conducted in different countries with diverse practice settings, including academic hospitals, national population-based cohorts, and clinical trials.
The researchers conducted a systematic review and meta-analysis to understand the utility of CLL-IPI tool in predicting OS and TTFT across each risk category of CLL patients.
They included nine studies with 7,843 patients to assess the impact of the CLL-IPI on overall survival. The patient distribution into the CLL-IPI risk categories was low risk (median 45.9%), intermediate risk (median 30%), high risk (median 16.5%), and very high risk (median 3.6%).
The researchers relied on 11 series comprising 7,383 patients to assess 5-year survival probability, which was 92% for low risk, 81% for intermediate risk, 60% for high risk, and 34% for very high risk. They used seven studies comprising 5,206 patients to assess TTFT and found that the probability of remaining treatment free at 5 years was 82% in the low-risk group, 45% in the intermediate-risk group, 30% in the high-risk group, and 16% in the very-high-risk group.
Although a significant step toward harmonizing international prognostication for CLL, additional studies validating the utility of the CLL-IPI for predicting OS in patients treated with targeted therapy are needed, they wrote.
The researchers reported having no financial disclosures.
FROM BLOOD
Hodgkin lymphoma survivors are at an increased risk of subsequent ER-negative breast cancer
Young women with primary Hodgkin lymphoma had an increased relative risk of estrogen receptor–positive breast cancer if they received radiotherapy and, irrespective of the type of treatment they got, an elevated risk of ER-negative breast cancer, based on results of a study based on patient records from 12 U.S. National Cancer Institute Surveillance, Epidemiology, and End Results registries.
Of 7,355 women diagnosed with primary Hodgkin lymphoma during 1973-2009 and aged 10-39 years, 377 patients subsequently were diagnosed with breast cancer at a mean age of 45 years; 57% of the cancers were ER positive, 34% were ER negative, and 9% had unknown/borderline ER status, Diana R. Withrow, PhD, and her colleagues from the radiation epidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute reported in JAMA Oncology.
Survivors of Hodgkin lymphoma had a greater relative risk of ER-negative (standardized incidence ratio, 5.8; 95% confidence interval, 4.8-6.9) than ER-positive breast cancer (SIR, 3.1; 95% CI, 2.7-3.5; P less than .001 for the difference), the researchers wrote.
For ER-positive disease, the increased SIR was observed only among women who had received radiotherapy for their Hodgkin lymphoma (SIR, 3.9; 95% CI, 3.4-4.5). In this group, the SIR for ER-positive disease was lower in the chemotherapy than in the no/unknown chemotherapy group (P = .04), said the researchers.
The authors acknowledged that lack of information on patient risk factors such as family history, reproductive factors, and hormone therapy, as well as detailed treatment information such as radiotherapy dose, fields, specific chemotherapeutic agents, and subsequent therapy is a limitation of the current study. Further research, including comprehensive treatment records, will lead to a better understanding of the association between treatment and breast cancer subtype in these patients, the researchers concluded.
None of the study authors reported any conflicts of interest.
SOURCE: Withrow D et al. doi: 10.1001/jamaoncol.2017.4887.
Young women with primary Hodgkin lymphoma had an increased relative risk of estrogen receptor–positive breast cancer if they received radiotherapy and, irrespective of the type of treatment they got, an elevated risk of ER-negative breast cancer, based on results of a study based on patient records from 12 U.S. National Cancer Institute Surveillance, Epidemiology, and End Results registries.
Of 7,355 women diagnosed with primary Hodgkin lymphoma during 1973-2009 and aged 10-39 years, 377 patients subsequently were diagnosed with breast cancer at a mean age of 45 years; 57% of the cancers were ER positive, 34% were ER negative, and 9% had unknown/borderline ER status, Diana R. Withrow, PhD, and her colleagues from the radiation epidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute reported in JAMA Oncology.
Survivors of Hodgkin lymphoma had a greater relative risk of ER-negative (standardized incidence ratio, 5.8; 95% confidence interval, 4.8-6.9) than ER-positive breast cancer (SIR, 3.1; 95% CI, 2.7-3.5; P less than .001 for the difference), the researchers wrote.
For ER-positive disease, the increased SIR was observed only among women who had received radiotherapy for their Hodgkin lymphoma (SIR, 3.9; 95% CI, 3.4-4.5). In this group, the SIR for ER-positive disease was lower in the chemotherapy than in the no/unknown chemotherapy group (P = .04), said the researchers.
The authors acknowledged that lack of information on patient risk factors such as family history, reproductive factors, and hormone therapy, as well as detailed treatment information such as radiotherapy dose, fields, specific chemotherapeutic agents, and subsequent therapy is a limitation of the current study. Further research, including comprehensive treatment records, will lead to a better understanding of the association between treatment and breast cancer subtype in these patients, the researchers concluded.
None of the study authors reported any conflicts of interest.
SOURCE: Withrow D et al. doi: 10.1001/jamaoncol.2017.4887.
Young women with primary Hodgkin lymphoma had an increased relative risk of estrogen receptor–positive breast cancer if they received radiotherapy and, irrespective of the type of treatment they got, an elevated risk of ER-negative breast cancer, based on results of a study based on patient records from 12 U.S. National Cancer Institute Surveillance, Epidemiology, and End Results registries.
Of 7,355 women diagnosed with primary Hodgkin lymphoma during 1973-2009 and aged 10-39 years, 377 patients subsequently were diagnosed with breast cancer at a mean age of 45 years; 57% of the cancers were ER positive, 34% were ER negative, and 9% had unknown/borderline ER status, Diana R. Withrow, PhD, and her colleagues from the radiation epidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute reported in JAMA Oncology.
Survivors of Hodgkin lymphoma had a greater relative risk of ER-negative (standardized incidence ratio, 5.8; 95% confidence interval, 4.8-6.9) than ER-positive breast cancer (SIR, 3.1; 95% CI, 2.7-3.5; P less than .001 for the difference), the researchers wrote.
For ER-positive disease, the increased SIR was observed only among women who had received radiotherapy for their Hodgkin lymphoma (SIR, 3.9; 95% CI, 3.4-4.5). In this group, the SIR for ER-positive disease was lower in the chemotherapy than in the no/unknown chemotherapy group (P = .04), said the researchers.
The authors acknowledged that lack of information on patient risk factors such as family history, reproductive factors, and hormone therapy, as well as detailed treatment information such as radiotherapy dose, fields, specific chemotherapeutic agents, and subsequent therapy is a limitation of the current study. Further research, including comprehensive treatment records, will lead to a better understanding of the association between treatment and breast cancer subtype in these patients, the researchers concluded.
None of the study authors reported any conflicts of interest.
SOURCE: Withrow D et al. doi: 10.1001/jamaoncol.2017.4887.
FROM JAMA ONCOLOGY
Key clinical point: .
Major finding: Survivors of Hodgkin lymphoma had a greater relative risk of ER-negative (standardized incidence ratio, 5.8) than ER-positive breast cancer (SIR, 3.1).
Study details: 7,355 women diagnosed with first primary Hodgkin lymphoma during 1973-2009, who were aged 10-39 years, and reported to 12 U.S. National Cancer Institute SEER registries.
Disclosures: None reported.
Source: Withrow D et al. doi: 10.1001/jamaoncolo.2017.4887.
Retroperitoneal lymphadenectomy did not impact OS and DFS for high risk, nonmetastatic renal cell carcinoma
according to a secondary analysis of the ASSURE adjuvant trial.
Patients were randomized to adjuvant sorafenib, sunitinib, or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial, and those at high risk – which was defined by cN+ disease or determined at their surgeon’s discretion – underwent LND. The primary objective was to assess the effect of LND on overall survival; secondary objectives included the effect of LND on disease-free survival and the benefit of adjuvant therapy vs. placebo in patients who underwent LND.
Overall, 1,943 patients were enrolled in the ASSURE trial, of which 36.1% (701 patients) underwent LND. A median of three lymph nodes (interquartile range, one to eight) was examined, and disease was pN+ in 23.4% patients. A majority of the patients were male (67.4%), with a median age of 56 years. Most (94.5%) patients underwent radical nephrectomy, and 57.2% patients had open surgery rather than laparoscopic. Tumors were clear cell in 81.7% of cases and Fuhrman grade 3-4 in 66.1%, investigators reported in the Journal Of Urology.
“There was no improvement in overall survival for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20). For patients who underwent lymphadenectomy with pN+ disease, no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy was overall safe, and did not increase the risk of surgical complications (14.2% vs. 13.4%; P = .63),” wrote Benjamin Ristau, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues. LND was independently associated with other markers of aggressive surgical resection, such as open surgery, radical nephrectomy, and adrenalectomy.
The role of lymphadenectomy in patients undergoing surgery for high-risk renal cell carcinoma remains elusive, the authors wrote. Future strategies include a prospective trial in which patients with high-risk renal cell carcinoma are randomized to specific lymphadenectomy templates.
This study was supported by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Christopher G. Wood reported conflicts of interest with Pfizer, Novartis and Argos. Other authors reported no conflicts of interest.
SOURCE: Ristau BT et al. J Urol. 2018 Jan. doi: 10.1016/j.juro.2017.07.042.
according to a secondary analysis of the ASSURE adjuvant trial.
Patients were randomized to adjuvant sorafenib, sunitinib, or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial, and those at high risk – which was defined by cN+ disease or determined at their surgeon’s discretion – underwent LND. The primary objective was to assess the effect of LND on overall survival; secondary objectives included the effect of LND on disease-free survival and the benefit of adjuvant therapy vs. placebo in patients who underwent LND.
Overall, 1,943 patients were enrolled in the ASSURE trial, of which 36.1% (701 patients) underwent LND. A median of three lymph nodes (interquartile range, one to eight) was examined, and disease was pN+ in 23.4% patients. A majority of the patients were male (67.4%), with a median age of 56 years. Most (94.5%) patients underwent radical nephrectomy, and 57.2% patients had open surgery rather than laparoscopic. Tumors were clear cell in 81.7% of cases and Fuhrman grade 3-4 in 66.1%, investigators reported in the Journal Of Urology.
“There was no improvement in overall survival for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20). For patients who underwent lymphadenectomy with pN+ disease, no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy was overall safe, and did not increase the risk of surgical complications (14.2% vs. 13.4%; P = .63),” wrote Benjamin Ristau, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues. LND was independently associated with other markers of aggressive surgical resection, such as open surgery, radical nephrectomy, and adrenalectomy.
The role of lymphadenectomy in patients undergoing surgery for high-risk renal cell carcinoma remains elusive, the authors wrote. Future strategies include a prospective trial in which patients with high-risk renal cell carcinoma are randomized to specific lymphadenectomy templates.
This study was supported by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Christopher G. Wood reported conflicts of interest with Pfizer, Novartis and Argos. Other authors reported no conflicts of interest.
SOURCE: Ristau BT et al. J Urol. 2018 Jan. doi: 10.1016/j.juro.2017.07.042.
according to a secondary analysis of the ASSURE adjuvant trial.
Patients were randomized to adjuvant sorafenib, sunitinib, or placebo in the ASSURE (Adjuvant Sorafenib and Sunitinib for Unfavorable Renal Carcinoma) trial, and those at high risk – which was defined by cN+ disease or determined at their surgeon’s discretion – underwent LND. The primary objective was to assess the effect of LND on overall survival; secondary objectives included the effect of LND on disease-free survival and the benefit of adjuvant therapy vs. placebo in patients who underwent LND.
Overall, 1,943 patients were enrolled in the ASSURE trial, of which 36.1% (701 patients) underwent LND. A median of three lymph nodes (interquartile range, one to eight) was examined, and disease was pN+ in 23.4% patients. A majority of the patients were male (67.4%), with a median age of 56 years. Most (94.5%) patients underwent radical nephrectomy, and 57.2% patients had open surgery rather than laparoscopic. Tumors were clear cell in 81.7% of cases and Fuhrman grade 3-4 in 66.1%, investigators reported in the Journal Of Urology.
“There was no improvement in overall survival for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20). For patients who underwent lymphadenectomy with pN+ disease, no improvement in overall or disease-free survival was observed for adjuvant therapy relative to placebo. Lymphadenectomy was overall safe, and did not increase the risk of surgical complications (14.2% vs. 13.4%; P = .63),” wrote Benjamin Ristau, MD, of Fox Chase Cancer Center in Philadelphia and his colleagues. LND was independently associated with other markers of aggressive surgical resection, such as open surgery, radical nephrectomy, and adrenalectomy.
The role of lymphadenectomy in patients undergoing surgery for high-risk renal cell carcinoma remains elusive, the authors wrote. Future strategies include a prospective trial in which patients with high-risk renal cell carcinoma are randomized to specific lymphadenectomy templates.
This study was supported by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Christopher G. Wood reported conflicts of interest with Pfizer, Novartis and Argos. Other authors reported no conflicts of interest.
SOURCE: Ristau BT et al. J Urol. 2018 Jan. doi: 10.1016/j.juro.2017.07.042.
FROM THE JOURNAL OF UROLOGY
Key clinical point: Lymphadenectomy did not improve overall survival or disease-free survival in patients with high-risk, nonmetastatic renal cell carcinoma who received either adjuvant therapy or placebo.
Major finding: There was no overall survival benefit for lymphadenectomy relative to no lymphadenectomy (HR, 1.14; 95% CI, 0.93-1.39; P = .20).
Study details: Patients enrolled prospectively in the ASSURE trial.
Disclosures: The study was funded by the National Cancer Institute of National Institutes of Health and the Canadian Cancer Research Institute. Although one author did report conflicts of interest with Pfizer, Novartis, and Argos, the rest reported no conflicts of interest.
Source: Ristau BT et al. J Urol. Jan 2018. doi: 10.1016/j.juro.2017.07.042.
Analysis of Twitter lung cancer content reveals opportunity for clinicians
Social media communication around lung cancer is focused primarily on cancer treatment and use of pharmaceutical and research interventions, followed closely by awareness, prevention, and risk topics, according to an analysis of Twitter conversation over a 10-day period.
Although awareness and risk prevention tweets were likely to contain cues toward action, “messages focused on treatment, end of life ... were significantly less likely to integrate cues for personal activity,” the investigators wrote. The report was published in Journal of the American College of Radiology.
The investigators collected 1.3 million unique Twitter messages between Sept. 30 and Oct. 9, 2016, that contained at least one of six keywords commonly used to describe cancer: cancer, chemo, tumor, malignant, biopsy, and metastasis. They then drew a random, proportional stratified sample of 3,000 messages (12.5%) for manual coding from the 23,926 messages posted that included keywords related to lung cancer. Tweets were examined by user type (individuals, media, and organizations) to identify content and structural message features.
Message content was most frequently related to treatment (32.1%), followed by awareness (22.9%), end of life (15.5%), prevention and risk information (13.3%), active cancer-unknown phase (7.6%), diagnosis (6.1%), early detection (2.7%), and survivorship (1%), Dr. Sutton and her colleagues reported.
“The large volume of messages containing content about pharmaceuticals suggests that Twitter is also a forum for sharing information and discussing emerging treatments. Importantly, treatment messages were shared primarily by individuals, suggesting that this online user community jointly includes members of the public as well as medical practitioners and companies who have an awareness of emerging treatment approaches, suggesting an opportunity for online engagement between these various groups (e.g., Lung Cancer Social Media #LCSM community and related chats),” the investigators wrote.
The National Science Foundation supported parts of this research. None of the authors reported any conflicts of interest.
SOURCE: Sutton J. et al., J Am Coll Radiol. 2018 Jan. doi: 10.1016/j.jacr.2017.09.043
Social media communication around lung cancer is focused primarily on cancer treatment and use of pharmaceutical and research interventions, followed closely by awareness, prevention, and risk topics, according to an analysis of Twitter conversation over a 10-day period.
Although awareness and risk prevention tweets were likely to contain cues toward action, “messages focused on treatment, end of life ... were significantly less likely to integrate cues for personal activity,” the investigators wrote. The report was published in Journal of the American College of Radiology.
The investigators collected 1.3 million unique Twitter messages between Sept. 30 and Oct. 9, 2016, that contained at least one of six keywords commonly used to describe cancer: cancer, chemo, tumor, malignant, biopsy, and metastasis. They then drew a random, proportional stratified sample of 3,000 messages (12.5%) for manual coding from the 23,926 messages posted that included keywords related to lung cancer. Tweets were examined by user type (individuals, media, and organizations) to identify content and structural message features.
Message content was most frequently related to treatment (32.1%), followed by awareness (22.9%), end of life (15.5%), prevention and risk information (13.3%), active cancer-unknown phase (7.6%), diagnosis (6.1%), early detection (2.7%), and survivorship (1%), Dr. Sutton and her colleagues reported.
“The large volume of messages containing content about pharmaceuticals suggests that Twitter is also a forum for sharing information and discussing emerging treatments. Importantly, treatment messages were shared primarily by individuals, suggesting that this online user community jointly includes members of the public as well as medical practitioners and companies who have an awareness of emerging treatment approaches, suggesting an opportunity for online engagement between these various groups (e.g., Lung Cancer Social Media #LCSM community and related chats),” the investigators wrote.
The National Science Foundation supported parts of this research. None of the authors reported any conflicts of interest.
SOURCE: Sutton J. et al., J Am Coll Radiol. 2018 Jan. doi: 10.1016/j.jacr.2017.09.043
Social media communication around lung cancer is focused primarily on cancer treatment and use of pharmaceutical and research interventions, followed closely by awareness, prevention, and risk topics, according to an analysis of Twitter conversation over a 10-day period.
Although awareness and risk prevention tweets were likely to contain cues toward action, “messages focused on treatment, end of life ... were significantly less likely to integrate cues for personal activity,” the investigators wrote. The report was published in Journal of the American College of Radiology.
The investigators collected 1.3 million unique Twitter messages between Sept. 30 and Oct. 9, 2016, that contained at least one of six keywords commonly used to describe cancer: cancer, chemo, tumor, malignant, biopsy, and metastasis. They then drew a random, proportional stratified sample of 3,000 messages (12.5%) for manual coding from the 23,926 messages posted that included keywords related to lung cancer. Tweets were examined by user type (individuals, media, and organizations) to identify content and structural message features.
Message content was most frequently related to treatment (32.1%), followed by awareness (22.9%), end of life (15.5%), prevention and risk information (13.3%), active cancer-unknown phase (7.6%), diagnosis (6.1%), early detection (2.7%), and survivorship (1%), Dr. Sutton and her colleagues reported.
“The large volume of messages containing content about pharmaceuticals suggests that Twitter is also a forum for sharing information and discussing emerging treatments. Importantly, treatment messages were shared primarily by individuals, suggesting that this online user community jointly includes members of the public as well as medical practitioners and companies who have an awareness of emerging treatment approaches, suggesting an opportunity for online engagement between these various groups (e.g., Lung Cancer Social Media #LCSM community and related chats),” the investigators wrote.
The National Science Foundation supported parts of this research. None of the authors reported any conflicts of interest.
SOURCE: Sutton J. et al., J Am Coll Radiol. 2018 Jan. doi: 10.1016/j.jacr.2017.09.043
FROM JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY
Key clinical point: In a random sample of Twitter conversation related to lung cancer, message content was most frequently related to treatment.
Major finding: Majority of tweets evaluated focused on lung cancer treatment and the use of pharmaceutical and research interventions, followed by awareness, prevention, and risk topics.
Study details: Random sample of 3,000 tweets posted in a 10-day period between Sept. 30 and Oct. 9, 2016. Lung cancer–specific tweets by user type (individuals, media, and organizations) were examined to identify content and structural message features.
Disclosures: The National Science Foundation supported parts of this research. None of the authors reported any conflicts of interest.
Source: Sutton J. et al., J Am Coll Radiol. 2018 Jan. doi: 10.1016/j.jacr.2017.09.043.