Andrew D. Bowser

For patients with atrial fibrillation with at least one risk factor besides gender, oral anticoagulation is the optimal choice of antithrombotic therapy, experts said in a comprehensive, updated guideline.

©Thinkstock

The 113-page guideline, published in the journal CHEST^®, provides antithrombotic treatment recommendations for atrial fibrillation based on different levels of risk for stroke and in a variety of clinical presentations.

Altogether, the new guidelines highlight 60 key recommendations from the 12-person expert panel, chaired by Gregory Y.H. Lip, MD, of the Institute of Cardiovascular Sciences, University of Birmingham (England).

To develop the guidelines, the panel conducted a systematic literature review of relevant articles released since the 2012 publication of Thrombolytic Therapy: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines (9th Edition).

Since that time, “there have been substantial developments in atrial fibrillation thromboprophylaxis, whether with regard to risk assessment, antithrombotic drugs, or non-drug approaches,” panelists said in their report.

The panel graded the quality of the new evidence found in the literature review, and then undertook a consensus development process. Each recommendation and statement required at least 80% consensus to pass.

Their treatment recommendations in the report are focused on three topic areas: stroke and bleeding risk assessment, antithrombotic therapy in general, and antithrombotic therapy in special situations, such as acute coronary syndrome and stenting, chronic atrial flutter, pregnancy, and chronic kidney disease.

Stroke prevention is the main priority in a “holistic approach” to management of atrial fibrillation, the panelists said in the report.

“Many of the risk factors leading to incident AF are also risk factors for ischemic stroke, and the promotion of an integrated or holistic approach to AF management is needed, incorporating stroke prevention, addressing symptoms and risk factor management,” they said.

No antithrombotic therapy is needed for patients who have atrial fibrillation without valvular heart disease, the panelists concluded.

For patients with at least one nongender CHA2DS2-VASc stroke risk factor, oral anticoagulation is recommended over aspirin, aspirin and clopidogrel, or no therapy, they said.

In high-risk patients, including males with two or more CHA₂DS₂-VASc risk factors and females with three or more, novel oral anticoagulants are recommended over adjusted-dose warfarin, they added.

At each patient contact, patients with atrial fibrillation should receive bleeding risk assessment starting with potentially modifiable risk factors such as uncontrolled blood pressure or excessive alcohol intake, according to the expert panel.

High-risk patients, as indicated by a HAS-BLED score of 3 or greater, should have more frequent and regular follow-up, they said.

The expert panel report concludes with a discussion on practical and patient-centered issues.

“Patient education is essential to provide patients with sufficient information to enable them to make an informed decision about whether or not they wish to take oral anticoagulants, and if they do, which oral anticoagulant they would prefer,” Dr. Lip and his colleagues said in their report.

Dr. Lip disclosed a potential conflict of interest with Boehringer Ingelheim. Expert panel members reported disclosures related to Boston Scientific, Medtronic, St. Jude Medical, Biotronik, MSD, Novartis, Pfizer, Bayer, Servier, Gilead, Bristol-Myers Squibb, AstraZeneca, and others.

SOURCE: Lip GYH et al. CHEST. 2018 Aug 21. pii: S0012-3692(18)32244-X.

For patients with atrial fibrillation with at least one risk factor besides gender, oral anticoagulation is the optimal choice of antithrombotic therapy, experts said in a comprehensive, updated guideline.

©Thinkstock

The 113-page guideline, published in the journal CHEST^®, provides antithrombotic treatment recommendations for atrial fibrillation based on different levels of risk for stroke and in a variety of clinical presentations.

Altogether, the new guidelines highlight 60 key recommendations from the 12-person expert panel, chaired by Gregory Y.H. Lip, MD, of the Institute of Cardiovascular Sciences, University of Birmingham (England).

To develop the guidelines, the panel conducted a systematic literature review of relevant articles released since the 2012 publication of Thrombolytic Therapy: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines (9th Edition).

Since that time, “there have been substantial developments in atrial fibrillation thromboprophylaxis, whether with regard to risk assessment, antithrombotic drugs, or non-drug approaches,” panelists said in their report.

The panel graded the quality of the new evidence found in the literature review, and then undertook a consensus development process. Each recommendation and statement required at least 80% consensus to pass.

Their treatment recommendations in the report are focused on three topic areas: stroke and bleeding risk assessment, antithrombotic therapy in general, and antithrombotic therapy in special situations, such as acute coronary syndrome and stenting, chronic atrial flutter, pregnancy, and chronic kidney disease.

Stroke prevention is the main priority in a “holistic approach” to management of atrial fibrillation, the panelists said in the report.

“Many of the risk factors leading to incident AF are also risk factors for ischemic stroke, and the promotion of an integrated or holistic approach to AF management is needed, incorporating stroke prevention, addressing symptoms and risk factor management,” they said.

No antithrombotic therapy is needed for patients who have atrial fibrillation without valvular heart disease, the panelists concluded.

For patients with at least one nongender CHA2DS2-VASc stroke risk factor, oral anticoagulation is recommended over aspirin, aspirin and clopidogrel, or no therapy, they said.

In high-risk patients, including males with two or more CHA₂DS₂-VASc risk factors and females with three or more, novel oral anticoagulants are recommended over adjusted-dose warfarin, they added.

At each patient contact, patients with atrial fibrillation should receive bleeding risk assessment starting with potentially modifiable risk factors such as uncontrolled blood pressure or excessive alcohol intake, according to the expert panel.

High-risk patients, as indicated by a HAS-BLED score of 3 or greater, should have more frequent and regular follow-up, they said.

The expert panel report concludes with a discussion on practical and patient-centered issues.

“Patient education is essential to provide patients with sufficient information to enable them to make an informed decision about whether or not they wish to take oral anticoagulants, and if they do, which oral anticoagulant they would prefer,” Dr. Lip and his colleagues said in their report.

Dr. Lip disclosed a potential conflict of interest with Boehringer Ingelheim. Expert panel members reported disclosures related to Boston Scientific, Medtronic, St. Jude Medical, Biotronik, MSD, Novartis, Pfizer, Bayer, Servier, Gilead, Bristol-Myers Squibb, AstraZeneca, and others.

SOURCE: Lip GYH et al. CHEST. 2018 Aug 21. pii: S0012-3692(18)32244-X.

For patients with atrial fibrillation with at least one risk factor besides gender, oral anticoagulation is the optimal choice of antithrombotic therapy, experts said in a comprehensive, updated guideline.

©Thinkstock

The 113-page guideline, published in the journal CHEST^®, provides antithrombotic treatment recommendations for atrial fibrillation based on different levels of risk for stroke and in a variety of clinical presentations.

Altogether, the new guidelines highlight 60 key recommendations from the 12-person expert panel, chaired by Gregory Y.H. Lip, MD, of the Institute of Cardiovascular Sciences, University of Birmingham (England).

To develop the guidelines, the panel conducted a systematic literature review of relevant articles released since the 2012 publication of Thrombolytic Therapy: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines (9th Edition).

Since that time, “there have been substantial developments in atrial fibrillation thromboprophylaxis, whether with regard to risk assessment, antithrombotic drugs, or non-drug approaches,” panelists said in their report.

The panel graded the quality of the new evidence found in the literature review, and then undertook a consensus development process. Each recommendation and statement required at least 80% consensus to pass.

Their treatment recommendations in the report are focused on three topic areas: stroke and bleeding risk assessment, antithrombotic therapy in general, and antithrombotic therapy in special situations, such as acute coronary syndrome and stenting, chronic atrial flutter, pregnancy, and chronic kidney disease.

Stroke prevention is the main priority in a “holistic approach” to management of atrial fibrillation, the panelists said in the report.

“Many of the risk factors leading to incident AF are also risk factors for ischemic stroke, and the promotion of an integrated or holistic approach to AF management is needed, incorporating stroke prevention, addressing symptoms and risk factor management,” they said.

No antithrombotic therapy is needed for patients who have atrial fibrillation without valvular heart disease, the panelists concluded.

For patients with at least one nongender CHA2DS2-VASc stroke risk factor, oral anticoagulation is recommended over aspirin, aspirin and clopidogrel, or no therapy, they said.

In high-risk patients, including males with two or more CHA₂DS₂-VASc risk factors and females with three or more, novel oral anticoagulants are recommended over adjusted-dose warfarin, they added.

At each patient contact, patients with atrial fibrillation should receive bleeding risk assessment starting with potentially modifiable risk factors such as uncontrolled blood pressure or excessive alcohol intake, according to the expert panel.

High-risk patients, as indicated by a HAS-BLED score of 3 or greater, should have more frequent and regular follow-up, they said.

The expert panel report concludes with a discussion on practical and patient-centered issues.

“Patient education is essential to provide patients with sufficient information to enable them to make an informed decision about whether or not they wish to take oral anticoagulants, and if they do, which oral anticoagulant they would prefer,” Dr. Lip and his colleagues said in their report.

Dr. Lip disclosed a potential conflict of interest with Boehringer Ingelheim. Expert panel members reported disclosures related to Boston Scientific, Medtronic, St. Jude Medical, Biotronik, MSD, Novartis, Pfizer, Bayer, Servier, Gilead, Bristol-Myers Squibb, AstraZeneca, and others.

SOURCE: Lip GYH et al. CHEST. 2018 Aug 21. pii: S0012-3692(18)32244-X.

PET imaging with an investigational tau tracer, ¹⁸F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.

PET with ¹⁸F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.

copyright alexdans/Thinkstock

SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.

PET imaging with an investigational tau tracer, ¹⁸F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.

PET with ¹⁸F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.

copyright alexdans/Thinkstock

SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.

PET imaging with an investigational tau tracer, ¹⁸F-flortaucipir, distinguished Alzheimer’s disease from other neurodegenerative disorders with a high degree of accuracy in a multicenter study.

PET with ¹⁸F-flortaucipir also outperformed structural MRI markers for Alzheimer’s disease (AD), and when compared against amyloid-beta (Abeta) biomarkers, showed higher specificity for an AD dementia diagnosis, researchers wrote in a report published online Sept. 18 in JAMA.

copyright alexdans/Thinkstock

SOURCE: Ossenkoppele R et al. JAMA. 2018;320(11):1151-62.

Proton therapy can help mitigate toxicity in adults with mediastinal lymphomas, but only when this modality offers a clear advantage over intensity-modulated radiotherapy, according to new guidelines from the International Lymphoma Radiation Oncology Group.

Proton therapy reduces radiation dose to organs at risk in certain clinical presentations, such as when the mediastinal target is on both sides of the heart. The advantages are not always clear in other situations, such as when the target spans the right side of the heart, or when the target is above the heart with no axillary involvement, according to guideline authors Bouthaina Dabaja, MD, professor and section chief of hematology in the department of radiation oncology at the University of Texas MD Anderson Cancer Center, Houston, and her colleagues.

“The limited availability of proton therapy calls for case selection based on a clear understanding of which cases will derive most benefit from proton therapy as compared to advanced photon techniques,” Dr. Dabaja and her coauthors said in the guidelines, which were published in the journal Blood (doi: 10.1182/blood-2018-03-837633).

Along with intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy, proton therapy presents “another opportunity” for more conformal dose distribution and better sparing of organs at risk, according to the consensus recommendations. Proton therapy can greatly benefit certain patients with mediastinal disease. These include young female patients to reduce breast dose and risk of a secondary breast cancer, patients at high risk of radiation-related toxicity due to previous treatment, and patients with disease spanning below the origin of the left main stem coronary artery that is anterior to, posterior to, or on the left side of the heart.

“The relation of disease to organs at risk determines the situations in which proton therapy is most beneficial,” the experts said in the guidelines. However, the consideration of proton therapy needs to factor the complexities of proton therapy planning, the need to manage uncertainties, and the “evolving nature of the technology,” which includes the development of pencil beam scanning.

While passive scattering proton therapy (PSPT) is the least complex delivery technique, it is challenging because beams can conform only to one side of the target; by contrast, the experts said, active mode pencil beam scanning proton therapy (PBSPT) potentially provides better conformity and sparing of organs at risk.

“Because treatment involves delivery of individual controlled spots, inhomogenous doses can be created deliberately,” the guideline authors said in their report.

However, motion management is “of prime importance” with PBSPT, which is more sensitive to density changes in the beam path as compared to PSPT, they added. Toward that end, physicians should pay close attention to evaluating intrafractional movement, which is frequently tied to the breathing cycle.

The guidelines list a total of 11 authors representing The University of Texas MD Anderson Cancer Center; University of Florida, Jacksonville; University of Pennsylvania, Philadelphia; University of Louisiana, Baton Rouge; Proton Therapy Center Czech, Prague; Motol University Hospital, Czech Republic; St. Thomas and Guy Hospital, London; Institut Curie, Paris; and Rigshospitalet, Copenhagen.

Dr. Dabaja and her guideline coauthors reported no funding or conflicts of interest.

Proton therapy can help mitigate toxicity in adults with mediastinal lymphomas, but only when this modality offers a clear advantage over intensity-modulated radiotherapy, according to new guidelines from the International Lymphoma Radiation Oncology Group.

Proton therapy reduces radiation dose to organs at risk in certain clinical presentations, such as when the mediastinal target is on both sides of the heart. The advantages are not always clear in other situations, such as when the target spans the right side of the heart, or when the target is above the heart with no axillary involvement, according to guideline authors Bouthaina Dabaja, MD, professor and section chief of hematology in the department of radiation oncology at the University of Texas MD Anderson Cancer Center, Houston, and her colleagues.

“The limited availability of proton therapy calls for case selection based on a clear understanding of which cases will derive most benefit from proton therapy as compared to advanced photon techniques,” Dr. Dabaja and her coauthors said in the guidelines, which were published in the journal Blood (doi: 10.1182/blood-2018-03-837633).

Along with intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy, proton therapy presents “another opportunity” for more conformal dose distribution and better sparing of organs at risk, according to the consensus recommendations. Proton therapy can greatly benefit certain patients with mediastinal disease. These include young female patients to reduce breast dose and risk of a secondary breast cancer, patients at high risk of radiation-related toxicity due to previous treatment, and patients with disease spanning below the origin of the left main stem coronary artery that is anterior to, posterior to, or on the left side of the heart.

“The relation of disease to organs at risk determines the situations in which proton therapy is most beneficial,” the experts said in the guidelines. However, the consideration of proton therapy needs to factor the complexities of proton therapy planning, the need to manage uncertainties, and the “evolving nature of the technology,” which includes the development of pencil beam scanning.

While passive scattering proton therapy (PSPT) is the least complex delivery technique, it is challenging because beams can conform only to one side of the target; by contrast, the experts said, active mode pencil beam scanning proton therapy (PBSPT) potentially provides better conformity and sparing of organs at risk.

“Because treatment involves delivery of individual controlled spots, inhomogenous doses can be created deliberately,” the guideline authors said in their report.

However, motion management is “of prime importance” with PBSPT, which is more sensitive to density changes in the beam path as compared to PSPT, they added. Toward that end, physicians should pay close attention to evaluating intrafractional movement, which is frequently tied to the breathing cycle.

The guidelines list a total of 11 authors representing The University of Texas MD Anderson Cancer Center; University of Florida, Jacksonville; University of Pennsylvania, Philadelphia; University of Louisiana, Baton Rouge; Proton Therapy Center Czech, Prague; Motol University Hospital, Czech Republic; St. Thomas and Guy Hospital, London; Institut Curie, Paris; and Rigshospitalet, Copenhagen.

Dr. Dabaja and her guideline coauthors reported no funding or conflicts of interest.

Proton therapy can help mitigate toxicity in adults with mediastinal lymphomas, but only when this modality offers a clear advantage over intensity-modulated radiotherapy, according to new guidelines from the International Lymphoma Radiation Oncology Group.

Proton therapy reduces radiation dose to organs at risk in certain clinical presentations, such as when the mediastinal target is on both sides of the heart. The advantages are not always clear in other situations, such as when the target spans the right side of the heart, or when the target is above the heart with no axillary involvement, according to guideline authors Bouthaina Dabaja, MD, professor and section chief of hematology in the department of radiation oncology at the University of Texas MD Anderson Cancer Center, Houston, and her colleagues.

“The limited availability of proton therapy calls for case selection based on a clear understanding of which cases will derive most benefit from proton therapy as compared to advanced photon techniques,” Dr. Dabaja and her coauthors said in the guidelines, which were published in the journal Blood (doi: 10.1182/blood-2018-03-837633).

Along with intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy, proton therapy presents “another opportunity” for more conformal dose distribution and better sparing of organs at risk, according to the consensus recommendations. Proton therapy can greatly benefit certain patients with mediastinal disease. These include young female patients to reduce breast dose and risk of a secondary breast cancer, patients at high risk of radiation-related toxicity due to previous treatment, and patients with disease spanning below the origin of the left main stem coronary artery that is anterior to, posterior to, or on the left side of the heart.

“The relation of disease to organs at risk determines the situations in which proton therapy is most beneficial,” the experts said in the guidelines. However, the consideration of proton therapy needs to factor the complexities of proton therapy planning, the need to manage uncertainties, and the “evolving nature of the technology,” which includes the development of pencil beam scanning.

While passive scattering proton therapy (PSPT) is the least complex delivery technique, it is challenging because beams can conform only to one side of the target; by contrast, the experts said, active mode pencil beam scanning proton therapy (PBSPT) potentially provides better conformity and sparing of organs at risk.

“Because treatment involves delivery of individual controlled spots, inhomogenous doses can be created deliberately,” the guideline authors said in their report.

However, motion management is “of prime importance” with PBSPT, which is more sensitive to density changes in the beam path as compared to PSPT, they added. Toward that end, physicians should pay close attention to evaluating intrafractional movement, which is frequently tied to the breathing cycle.

The guidelines list a total of 11 authors representing The University of Texas MD Anderson Cancer Center; University of Florida, Jacksonville; University of Pennsylvania, Philadelphia; University of Louisiana, Baton Rouge; Proton Therapy Center Czech, Prague; Motol University Hospital, Czech Republic; St. Thomas and Guy Hospital, London; Institut Curie, Paris; and Rigshospitalet, Copenhagen.

Dr. Dabaja and her guideline coauthors reported no funding or conflicts of interest.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

The immune microenvironment of metastatic breast cancer lesions is relatively inert and depleted versus primary tumors, results of a recent study suggest.

“These results predict that immune therapy may be more successful in early stage breast cancers rather than in metastatic disease,” Lajos Pusztai, MD, and study coinvestigators reported in Annals of Oncology.

However, metastatic breast cancers showed high expression levels of some targetable molecules that may provide a “foundation for rational immunotherapy combination strategies,” wrote Dr. Pusztai, director of breast cancer translational research at Yale Cancer Center, New Haven, Conn., and his coinvestigators.

The investigators looked at tumor PD-L1 protein expression, tumor infiltrating lymphocyte (TIL) count, and mRNA expression for 730 immune-related genes in both primary and metastatic cancer samples obtained from pathologists at Yale.

The study included one cohort with full sections of paired metastatic and primary tumors from 45 patients, and a second cohort of tissue microarrays from 55 other patients.

Compared with primary lesions, metastatic lesions had substantially lower levels of PD-L1 expression and TIL counts, the investigators found.

Staining of PD-L1 was primarily seen in stromal immune cells, rather than tumor cells, according to investigators. The median stromal PD-L1 positivity was 14% for metastases and 52% for primary tumors in the first cohort (P = .0004), and 7% for metastases and 22% for primary tumors in the second cohort (P = .03).

They also reported significant decreased TIL counts in metastatic lesions for both the first (P = .026) and second (P = .089) cohorts, the report shows.

Immune gene expression profiling results, similarly, showed that most immune cell types and functions were “depleted” in the metastatic lesions, including a decreased mRNA expression of CTLA4, Dr. Pusztai and his colleagues reported.

The “lesser immunogenicity” of metastatic breast cancer cells was shown by decreased expression of immune proteasome and MHC class I genes, along with increased expression of HLA-E, which has been shown to suppress immunity, and reduced presence of dendritic cells, they said.

However, they also found high expression of targetable molecules in metastatic lesions. Those included macrophage markers such as CD68 and CD163, cytokine ligand/receptor pairs that mediate pro-tumorigenic effects, such as CCL2/CCR2 and CXCR4/CXCL12, and signaling molecules such as STAT-3 and JAK2, among others.

“We suggest that targeting these molecules may lead to synergy with PD1/PD-L1 blockade in metastatic breast cancer,” they wrote.

The work by Dr. Pusztai and his colleagues was supported by the Breast Cancer Research Foundation, Susan G Komen for the Cure, Department of Defense Breast Cancer Research Program Awards, and the Rosztoczy Foundation. The authors declared no conflicts of interest.

SOURCE: Szekely B, et al. Ann Oncol. 2018 Sep 10. doi: 10.1093/annonc/mdy399.

A substantial proportion of patients with follicular lymphoma managed with watchful waiting develop organ dysfunction or transformation that may negatively impact survival outcomes, results of a retrospective study suggest.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

About one-quarter of patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival that could not be predicted based on baseline characteristics, the study authors reported in Clinical Lymphoma, Myeloma & Leukemia.

The study confirmed certain benefits of watchful waiting, including a low risk of progression and an “excellent” rate of overall survival, the investigators said.

However, the substantial rate of organ dysfunction and transformation in a subset of patients is “clinically meaningful for informed decision making,” reported Gwynivere A. Davies, MD, of the University of Calgary (Alta.), and her coauthors.

“While consenting patients to initial [watchful waiting], patients need to be informed about the risk for these adverse events, as well as receiving education and the need for close monitoring regarding symptoms that may indicate serious progression events,” Dr. Davies and her coauthors wrote.

Alternatively, rituximab chemotherapy, with or without rituximab maintenance, might be warranted for watchful waiting patients with clear disease progression before organ dysfunction or transformation events, despite not meeting high-tumor burden therapy indications.

SOURCE: Davies GA et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 28. doi: 10.1016/j.clml.2018.08.015.

A substantial proportion of patients with follicular lymphoma managed with watchful waiting develop organ dysfunction or transformation that may negatively impact survival outcomes, results of a retrospective study suggest.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

About one-quarter of patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival that could not be predicted based on baseline characteristics, the study authors reported in Clinical Lymphoma, Myeloma & Leukemia.

The study confirmed certain benefits of watchful waiting, including a low risk of progression and an “excellent” rate of overall survival, the investigators said.

However, the substantial rate of organ dysfunction and transformation in a subset of patients is “clinically meaningful for informed decision making,” reported Gwynivere A. Davies, MD, of the University of Calgary (Alta.), and her coauthors.

“While consenting patients to initial [watchful waiting], patients need to be informed about the risk for these adverse events, as well as receiving education and the need for close monitoring regarding symptoms that may indicate serious progression events,” Dr. Davies and her coauthors wrote.

Alternatively, rituximab chemotherapy, with or without rituximab maintenance, might be warranted for watchful waiting patients with clear disease progression before organ dysfunction or transformation events, despite not meeting high-tumor burden therapy indications.

SOURCE: Davies GA et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 28. doi: 10.1016/j.clml.2018.08.015.

A substantial proportion of patients with follicular lymphoma managed with watchful waiting develop organ dysfunction or transformation that may negatively impact survival outcomes, results of a retrospective study suggest.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

About one-quarter of patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival that could not be predicted based on baseline characteristics, the study authors reported in Clinical Lymphoma, Myeloma & Leukemia.

The study confirmed certain benefits of watchful waiting, including a low risk of progression and an “excellent” rate of overall survival, the investigators said.

However, the substantial rate of organ dysfunction and transformation in a subset of patients is “clinically meaningful for informed decision making,” reported Gwynivere A. Davies, MD, of the University of Calgary (Alta.), and her coauthors.

“While consenting patients to initial [watchful waiting], patients need to be informed about the risk for these adverse events, as well as receiving education and the need for close monitoring regarding symptoms that may indicate serious progression events,” Dr. Davies and her coauthors wrote.

Alternatively, rituximab chemotherapy, with or without rituximab maintenance, might be warranted for watchful waiting patients with clear disease progression before organ dysfunction or transformation events, despite not meeting high-tumor burden therapy indications.

SOURCE: Davies GA et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 28. doi: 10.1016/j.clml.2018.08.015.

A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.

Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.

Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.

The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.

The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.

Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.

SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.

A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.

Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.

Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.

The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.

The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.

Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.

SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.

A wide variety of hematologic, dermatologic, and solid organ malignancies are associated with pruritus, a large, single-center, retrospective study suggests.

Blacks with pruritus had a higher odds ratio of hematologic malignancies, among others, while whites had higher likelihood of liver, gastrointestinal, respiratory and gynecologic cancers, results of the study show.

Blacks with pruritus had higher ORs for hematologic and soft tissue malignancies including those of the muscle, fat, and peripheral nerve, investigators said, while whites had higher ORs for skin and liver malignancies.

The investigators also looked at the prevalence of skin eruptions in patients with pruritus and malignancy. “Eruption is variable by malignancy type and points to differing underlying mechanisms of pruritus,” they reported.

The highest rates of skin eruption were in patients with myeloid leukemia at 66%, followed by bone cancers at 58%, lymphocytic leukemia at 57%, multiple myeloma at 53%, and bronchus at 53%. The lowest rates of skin eruption were in patients with gallbladder and biliary tract, colon, pancreas, and liver malignancies.

Dr. Kwatra reported that he is an advisory board member for Menlo Therapeutics and Trevi Therapeutics.

SOURCE: Kwatra SG et al. J Am Acad Dermatol. 2018 Sep 11. doi: 10.1016/j.jaad.2018.08.044.

Multiday epileptic seizure cycles may occur in a substantial number of individuals with epilepsy, results of a retrospective cohort study suggest.

While about 80% of patients in the study showed circadian modulation of their seizure rates, a substantial portion showed strong circaseptan (7 day) rhythms, according to the study’s senior author, Mark J. Cook, MD, of the department of medicine at St. Vincent’s Hospital, Melbourne.

Significant circaseptan cycles were seen in more than 20% of patients in one analysis from the study, which Dr. Cook and his colleagues reported in the Lancet Neurology.

The high prevalence of multiday seizure cycles could present an opportunity to improve treatment through development of patient-specific chronotherapy or the timing of medication to match when seizures would be most likely. “Even without fully understanding the mechanisms of seizure cycles, temporal patterns can be incorporated into patient management plans,” Dr. Cook said in a news release.

The study by Dr. Cook and his colleagues was based on two seizure datasets. One was a U.S. cohort of 1,118 patients who self-reported at least 100 episodes through the SeizureTracker website or mobile app. The other was an Australian cohort of 12 patients with focal epilepsy who had at least 30 recorded seizures in a study of an implanted electrocorticography device that tracked them between 6 months and 3 years.

In the SeizureTracker data, 86% of participants had at least one significant cycle in their seizure times, and 64% had more than one cycle. Most of the cycles (80%) were circadian, while 21% of people had significant 7-day cycles in one analysis using the Hodges-Ajne test, a statistical method used to assess circular data.

“Many patients also showed some evidence of cycles lasting up to a month,” wrote Dr. Cook and his coauthors.

A confirmatory analysis using Monte Carlo simulation found that 7% of people, or 77 individuals, had significant 7-day cycles. “The probability that 77 patients would randomly share a specific cycle [such as a 7-day cycle] is infinitesimal,” the authors wrote.

In the implantable device study, 11 out of 12 patients had strong rhythms at 24 hours, according to the investigators, while 1 had a significant cycle of exactly 1 week, and 2 others had cycles of approximately 1 week.

“Some people had stronger rhythms at time scales longer than 24 hours, which suggests that circadian regulation was not necessarily the strongest modulating factor of epileptic activity,” the investigators wrote.

The cause of longer seizure cycles remains unclear, according to the investigators, though peak seizure times might be linked to behavioral changes such as varying stress levels over the course of the week, seasonal changes in sleep quality, or biologic drivers such as menstruation.

“A better understanding of seizure cycles might provide new targets for treatment,” they wrote.

Funding for the study came from the Australian National Health and Medical Research Council. Dr. Cook declared no competing interests, while his coauthors reported support from sources outside of this study. One study author is a cofounder of SeizureTracker.com.

SOURCE: Cook MJ et al. Lancet Neurol. 2018 Sep 12. doi: 10.1016/S1474-4422(18)30274-6.

Multiday epileptic seizure cycles may occur in a substantial number of individuals with epilepsy, results of a retrospective cohort study suggest.

While about 80% of patients in the study showed circadian modulation of their seizure rates, a substantial portion showed strong circaseptan (7 day) rhythms, according to the study’s senior author, Mark J. Cook, MD, of the department of medicine at St. Vincent’s Hospital, Melbourne.

Significant circaseptan cycles were seen in more than 20% of patients in one analysis from the study, which Dr. Cook and his colleagues reported in the Lancet Neurology.

The high prevalence of multiday seizure cycles could present an opportunity to improve treatment through development of patient-specific chronotherapy or the timing of medication to match when seizures would be most likely. “Even without fully understanding the mechanisms of seizure cycles, temporal patterns can be incorporated into patient management plans,” Dr. Cook said in a news release.

The study by Dr. Cook and his colleagues was based on two seizure datasets. One was a U.S. cohort of 1,118 patients who self-reported at least 100 episodes through the SeizureTracker website or mobile app. The other was an Australian cohort of 12 patients with focal epilepsy who had at least 30 recorded seizures in a study of an implanted electrocorticography device that tracked them between 6 months and 3 years.

In the SeizureTracker data, 86% of participants had at least one significant cycle in their seizure times, and 64% had more than one cycle. Most of the cycles (80%) were circadian, while 21% of people had significant 7-day cycles in one analysis using the Hodges-Ajne test, a statistical method used to assess circular data.

“Many patients also showed some evidence of cycles lasting up to a month,” wrote Dr. Cook and his coauthors.

A confirmatory analysis using Monte Carlo simulation found that 7% of people, or 77 individuals, had significant 7-day cycles. “The probability that 77 patients would randomly share a specific cycle [such as a 7-day cycle] is infinitesimal,” the authors wrote.

In the implantable device study, 11 out of 12 patients had strong rhythms at 24 hours, according to the investigators, while 1 had a significant cycle of exactly 1 week, and 2 others had cycles of approximately 1 week.

“Some people had stronger rhythms at time scales longer than 24 hours, which suggests that circadian regulation was not necessarily the strongest modulating factor of epileptic activity,” the investigators wrote.

The cause of longer seizure cycles remains unclear, according to the investigators, though peak seizure times might be linked to behavioral changes such as varying stress levels over the course of the week, seasonal changes in sleep quality, or biologic drivers such as menstruation.

“A better understanding of seizure cycles might provide new targets for treatment,” they wrote.

Funding for the study came from the Australian National Health and Medical Research Council. Dr. Cook declared no competing interests, while his coauthors reported support from sources outside of this study. One study author is a cofounder of SeizureTracker.com.

SOURCE: Cook MJ et al. Lancet Neurol. 2018 Sep 12. doi: 10.1016/S1474-4422(18)30274-6.

Multiday epileptic seizure cycles may occur in a substantial number of individuals with epilepsy, results of a retrospective cohort study suggest.

While about 80% of patients in the study showed circadian modulation of their seizure rates, a substantial portion showed strong circaseptan (7 day) rhythms, according to the study’s senior author, Mark J. Cook, MD, of the department of medicine at St. Vincent’s Hospital, Melbourne.

Significant circaseptan cycles were seen in more than 20% of patients in one analysis from the study, which Dr. Cook and his colleagues reported in the Lancet Neurology.

The high prevalence of multiday seizure cycles could present an opportunity to improve treatment through development of patient-specific chronotherapy or the timing of medication to match when seizures would be most likely. “Even without fully understanding the mechanisms of seizure cycles, temporal patterns can be incorporated into patient management plans,” Dr. Cook said in a news release.

The study by Dr. Cook and his colleagues was based on two seizure datasets. One was a U.S. cohort of 1,118 patients who self-reported at least 100 episodes through the SeizureTracker website or mobile app. The other was an Australian cohort of 12 patients with focal epilepsy who had at least 30 recorded seizures in a study of an implanted electrocorticography device that tracked them between 6 months and 3 years.

In the SeizureTracker data, 86% of participants had at least one significant cycle in their seizure times, and 64% had more than one cycle. Most of the cycles (80%) were circadian, while 21% of people had significant 7-day cycles in one analysis using the Hodges-Ajne test, a statistical method used to assess circular data.

“Many patients also showed some evidence of cycles lasting up to a month,” wrote Dr. Cook and his coauthors.

A confirmatory analysis using Monte Carlo simulation found that 7% of people, or 77 individuals, had significant 7-day cycles. “The probability that 77 patients would randomly share a specific cycle [such as a 7-day cycle] is infinitesimal,” the authors wrote.

In the implantable device study, 11 out of 12 patients had strong rhythms at 24 hours, according to the investigators, while 1 had a significant cycle of exactly 1 week, and 2 others had cycles of approximately 1 week.

“Some people had stronger rhythms at time scales longer than 24 hours, which suggests that circadian regulation was not necessarily the strongest modulating factor of epileptic activity,” the investigators wrote.

The cause of longer seizure cycles remains unclear, according to the investigators, though peak seizure times might be linked to behavioral changes such as varying stress levels over the course of the week, seasonal changes in sleep quality, or biologic drivers such as menstruation.

“A better understanding of seizure cycles might provide new targets for treatment,” they wrote.

Funding for the study came from the Australian National Health and Medical Research Council. Dr. Cook declared no competing interests, while his coauthors reported support from sources outside of this study. One study author is a cofounder of SeizureTracker.com.

SOURCE: Cook MJ et al. Lancet Neurol. 2018 Sep 12. doi: 10.1016/S1474-4422(18)30274-6.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

Photo by Bill Branson

In a phase 3 study, levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias who received intensive chemotherapy.

However, the risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children who underwent hematopoietic stem cell transplant (HSCT).

Sarah Alexander, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and her colleagues reported these findings in JAMA.

This multicenter, randomized trial (ACCL0934) enrolled patients aged 6 months to 21 years.

There were 200 patients with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were set to receive chemotherapy and 424 patients who were to receive a myeloablative autologous or allogeneic HSCT.

The acute leukemia patients were randomized to receive no prophylaxis (n=100) or levofloxacin prophylaxis (n=100) for two consecutive cycles of chemotherapy.

The HSCT recipients were randomized to receive no prophylaxis (n=214) or levofloxacin prophylaxis (n=210) during one HSCT procedure.

Results

In the primary analysis of the acute leukemia group (n=195), the incidence of bacteremia was 21.9% for those randomized to levofloxacin and 43.4% for those who did not receive prophylaxis (P=0.001).

In the primary analysis of the HSCT group (n=418), the incidence of bacteremia was 11.0% in the levofloxacin arm and 17.3% in the control arm (P=0.06).

However, a post hoc analysis accounting for time at risk showed a significant difference in favor of prophylaxis in both the acute leukemia and HSCT groups and a similar effect size between groups.

For the acute leukemia group, the rate of bacteremic episodes in the post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.008).

In the HSCT group, the rate of bacteremic episodes was 5.3 versus 10.0 per 1,000 patient-days in the prophylaxis and control arms, respectively (P=0.02).

The researchers said it is possible that the effect of prophylaxis was similar between the HSCT and acute leukemia groups, but there was reduced power to detect a significant difference because of fewer events among HSCT recipients.

However, the differences between the HSCT and acute leukemia groups in the primary analysis might also be explained by differences in supportive care measures or infections with pathogens that had differential sensitivity to levofloxacin.

The researchers noted that levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk.

Dr. Alexander and her colleagues also said further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits.

In the current study, there were 23 serious adverse events reported in 8 patients. Twelve of these events, occurring in two patients, may have been related to levofloxacin.

This research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

©Raimond Spekking

In a prospective study, Hispanic pediatric patients with acute lymphoblastic leukemia (ALL) had a risk of methotrexate-induced neurotoxicity that was more than twice the risk observed in non-Hispanic white patients.

However, there was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients.

There were no cases of neurotoxicity among patients of other races/ethnicities.

Michael E. Scheurer, PhD, of Baylor College of Medicine in Houston, Texas, and his colleagues conducted this study and detailed the results in Clinical Cancer Research.

The study included 280 patients with newly diagnosed ALL. Most patients (85.7%) had B-ALL, 10.7% had T-ALL, and 3.6% had lymphoblastic lymphoma.

Nearly half of the patients (48.2%) were Hispanic, 36.2% were non-Hispanic white, 8.3% were non-Hispanic black, and 7.3% were non-Hispanic “other.”

The patients, who had a mean age of 8.4 years at diagnosis, were treated with modern ALL protocols and were followed from diagnosis to the start of maintenance/continuation therapy.

Methotrexate neurotoxicity was seen in 39 patients at the time of the analysis. Of those patients, 29 (74.4%) were Hispanic.

Compared with non-Hispanic whites, Hispanics had a high risk of methotrexate neurotoxicity, even after the researchers accounted for age, sex, ALL risk stratification, and other factors. The adjusted hazard ratio (HR) was 2.43 (P=0.036).

“We had observed that our Hispanic patients tended to experience neurotoxicity more often than other groups, but we were surprised to see the magnitude of the difference,” Dr. Scheurer said.

There was no significant difference in methotrexate neurotoxicity between non-Hispanic black patients and non-Hispanic white patients. The adjusted HR for non-Hispanic black patients was 1.23 (P=0.80).

Patients in the “other” racial/ethnic group did not experience any neurotoxic events.

All nine patients who experienced a second neurotoxic event were Hispanic.

Patients who had neurotoxicity received an average of 2.25 fewer doses of intrathecal methotrexate (P<0.01) and 1.81 fewer doses of intravenous methotrexate (P=0.084) than patients without neurotoxicity.

About three-quarters (74.4%) of patients experiencing methotrexate neurotoxicity received leucovorin rescue, according to the investigators, who noted that leucovorin may interact with methotrexate and reduce its efficacy.

Relapse occurred in 15.4% (6/39) of patients with neurotoxicity and 2.1% (13/241) of patients with no neurotoxicity (P=0.0038).

The investigators said these findings add to the growing body of evidence that Hispanics and other minority pediatric patients with ALL experience “significant disparities” in treatment outcomes.

It remains unclear why Hispanic patients would have a higher risk of methotrexate neurotoxicity, and that must be explored in future studies, the investigators said.

The team is currently investigating whether biomarkers could be used to identify patients at risk of methotrexate neurotoxicity.

“Biomarkers may someday allow us to identify patients upfront, before even beginning therapy, who might be at risk for such outcomes,” Dr. Scheurer said. “If we can identify these at-risk patients, we can potentially employ strategies to either fully prevent or mitigate these toxicities.”

This research was supported by the National Institutes of Health and Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, a St. Baldrick’s Foundation Consortium Research Grant. The researchers said they had no potential conflicts of interest.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.

Levofloxacin prophylaxis significantly reduced bacteremia in children with acute leukemias receiving intensive chemotherapy, according to results of a multicenter, randomized phase 3 trial.

Risk of bacteremia was not significantly reduced with levofloxacin in another cohort of children undergoing hematopoietic stem cell transplantation (HSCT), although a post hoc analysis accounting for time at risk did show a significant difference, according to results of this Children’s Oncology Group (COG) trial.

The reduction in risk for children with acute leukemias was similar to findings of adult studies showing the benefit of prophylactic antibiotics in patients with cancer-related neutropenia, said Sarah Alexander, MD, of the division of hematology/oncology, the Hospital for Sick Children, Toronto, and her coinvestigators.

Before this COG study, data on prophylactic antibiotics in children with cancer were limited to several small, single-group observational studies, Dr. Alexander and her coauthors wrote in JAMA.

Bacteremia was the primary outcome of the COG study, according to the investigators, because of its link to sepsis, increased health care utilization, and infection-related mortality. “Consequently, this outcome is meaningful to both clinicians and patients,” the investigators noted.

The multicenter, randomized, open-label phase 3 trial (ACCL0934) enrolled patients aged 6 months to 21 years, including 200 with acute leukemias (acute myeloid leukemia or relapsed acute lymphoblastic leukemia) who were to receive at least two intensive chemotherapy cycles, and 424 who were to receive a myeloablative autologous or allogeneic HSCT.

In the final analysis of the acute leukemias group, which included 195 patients, likelihood of bacteremia was 21.9% for those randomized to levofloxacin prophylaxis, versus 43.4% for no prophylaxis (P = 0.001).

In the final analysis of the HSCT group, which included 418 patients, likelihood of bacteremia was not significantly different, at 11.0% for levofloxacin prophylaxis, versus 17.3% for no prophylaxis (P = 0.06).

“Levofloxacin prophylaxis was effective at reducing the risk of bacteremia among patients with acute leukemia, but not among patients undergoing HSCT,” Dr. Armstrong and her coauthors said.

A post hoc analysis accounting for time at risk, however, showed a significant difference in favor of prophylaxis in both groups and a similar effect size between groups, according to investigators.

For the acute leukemias group, the rate of bacteremic episodes in that post hoc analysis was 4.9 versus 9.4 per 1,000 patient-days in the prophylaxis and no prophylaxis arms, respectively (P = 0.008). In the HSCT group, the rate was 5.3 versus 10.0 bacteremias per 1,000 patient-days in the prophylaxis and no prophylaxis arms (P = .02).

The similar effect size suggests that in the primary analysis, there was reduced power to detect a significant difference in the HSCT group because of fewer events, driven partly by a shorter duration of neutropenia in that group, Dr. Armstrong and her associates said.

“However, it is also plausible that the leukemia and HSCT groups had different supportive care measures or were infected with pathogens that had differential sensitivity to levofloxacin resulting in different efficacy of levofloxacin in the 2 groups,” they added.

Levofloxacin-resistant pathogens, such as viridans group streptococcal isolates and several Gram-negative isolates, often were detected in patients who had bacteremia events despite prophylaxis. This suggests that other interventions in combination with levofloxacin prophylaxis are probably needed to further decrease risk, the investigators said.

Further randomized studies are needed to better understand the risks of levofloxacin in relation to its benefits, according to the investigators, who reported 23 serious adverse events in 8 patients, 11 of which were considered unrelated or unlikely to be related to levofloxacin.

“The adoption of antibacterial prophylaxis is tempered by potential negative consequences including Clostridium difficile-associated diarrhea, bacterial resistance, and musculoskeletal toxicities,” Dr. Armstrong and her colleagues noted.

The research was supported by grants from the Community Clinical Oncology Program and National Cancer Institute. Dr. Alexander reported no disclosures. Coauthors reported disclosures related to Bristol-Myers Squibb, Chimerix, Jazz Pharmaceuticals, and the Children’s Oncology Group.

SOURCE: Alexander S, et al . JAMA. 2018;320(10):995-1004.