Advances in radiation treatment have led to better targeting, minimizing the dose to healthy tissue. For patients with Hodgkin lymphoma (HL), pretreatment scanning with positron emission tomography and computed tomography (PET/CT) has become the gold standard, say researchers from University of Florida, in determining the extent of HL. Because HL may recur at the site of the original cancer, the scans are important to accurately capture the scope of the disease. Moreover, the researchers say pretreatment PET/CT may reduce disease progression.

Related: Study Points to Risk Factors for Lymphoma

In their study of 37 patients with stage I or II HL, 31 had PET/CT before chemotherapy. Two of the remaining 6 had PET/CT done within 5 days after chemotherapy was started. Median follow-up was 46 months.

The 4-year rate of relapse-free survival was 92%. Patients who did not receive pretreatment PET/CT were more likely to have a relapse (67%). Of 4 recurrences, 3 were within 12 months of follow-up; 1 developed 5 years after treatment.

Among the 6 patients who did not have a baseline PET/CT scan, all 3 recurrences were in lymph node regions outside of, but adjacent to, the radiation field. None of the 6 experienced an in-field treatment failure.

Related: Development and Implementation of a Veterans’ Cancer Survivorship Program

Long-term survivors of HL are vulnerable to late adverse effects, the researchers note, and that fact is “the impetus behind efforts to reduce radiation exposure to organs at risk.” They cite studies that have found that PET/CT scans, compared with using only pretreatment contrast-enhanced CT scans, can alter the staging in 10% to 30% of patients with HL. Their study, the researchers add, helps support the National Comprehensive Cancer Network guidelines that advise prechemotherapy PET/CT imaging in staging all HL patients. Not doing complete staging, the researchers say, puts patients at “unnecessary, and in some instances preventable, risk for recurrence.”

Source:

Figura N,  Flampouri S, Mendenhall NP, et al. Adv Radiat Oncol. 2017;1-16.

Advances in radiation treatment have led to better targeting, minimizing the dose to healthy tissue. For patients with Hodgkin lymphoma (HL), pretreatment scanning with positron emission tomography and computed tomography (PET/CT) has become the gold standard, say researchers from University of Florida, in determining the extent of HL. Because HL may recur at the site of the original cancer, the scans are important to accurately capture the scope of the disease. Moreover, the researchers say pretreatment PET/CT may reduce disease progression.

Related: Study Points to Risk Factors for Lymphoma

In their study of 37 patients with stage I or II HL, 31 had PET/CT before chemotherapy. Two of the remaining 6 had PET/CT done within 5 days after chemotherapy was started. Median follow-up was 46 months.

The 4-year rate of relapse-free survival was 92%. Patients who did not receive pretreatment PET/CT were more likely to have a relapse (67%). Of 4 recurrences, 3 were within 12 months of follow-up; 1 developed 5 years after treatment.

Among the 6 patients who did not have a baseline PET/CT scan, all 3 recurrences were in lymph node regions outside of, but adjacent to, the radiation field. None of the 6 experienced an in-field treatment failure.

Related: Development and Implementation of a Veterans’ Cancer Survivorship Program

Long-term survivors of HL are vulnerable to late adverse effects, the researchers note, and that fact is “the impetus behind efforts to reduce radiation exposure to organs at risk.” They cite studies that have found that PET/CT scans, compared with using only pretreatment contrast-enhanced CT scans, can alter the staging in 10% to 30% of patients with HL. Their study, the researchers add, helps support the National Comprehensive Cancer Network guidelines that advise prechemotherapy PET/CT imaging in staging all HL patients. Not doing complete staging, the researchers say, puts patients at “unnecessary, and in some instances preventable, risk for recurrence.”

Source:

Figura N,  Flampouri S, Mendenhall NP, et al. Adv Radiat Oncol. 2017;1-16.

Advances in radiation treatment have led to better targeting, minimizing the dose to healthy tissue. For patients with Hodgkin lymphoma (HL), pretreatment scanning with positron emission tomography and computed tomography (PET/CT) has become the gold standard, say researchers from University of Florida, in determining the extent of HL. Because HL may recur at the site of the original cancer, the scans are important to accurately capture the scope of the disease. Moreover, the researchers say pretreatment PET/CT may reduce disease progression.

Related: Study Points to Risk Factors for Lymphoma

In their study of 37 patients with stage I or II HL, 31 had PET/CT before chemotherapy. Two of the remaining 6 had PET/CT done within 5 days after chemotherapy was started. Median follow-up was 46 months.

The 4-year rate of relapse-free survival was 92%. Patients who did not receive pretreatment PET/CT were more likely to have a relapse (67%). Of 4 recurrences, 3 were within 12 months of follow-up; 1 developed 5 years after treatment.

Among the 6 patients who did not have a baseline PET/CT scan, all 3 recurrences were in lymph node regions outside of, but adjacent to, the radiation field. None of the 6 experienced an in-field treatment failure.

Related: Development and Implementation of a Veterans’ Cancer Survivorship Program

Long-term survivors of HL are vulnerable to late adverse effects, the researchers note, and that fact is “the impetus behind efforts to reduce radiation exposure to organs at risk.” They cite studies that have found that PET/CT scans, compared with using only pretreatment contrast-enhanced CT scans, can alter the staging in 10% to 30% of patients with HL. Their study, the researchers add, helps support the National Comprehensive Cancer Network guidelines that advise prechemotherapy PET/CT imaging in staging all HL patients. Not doing complete staging, the researchers say, puts patients at “unnecessary, and in some instances preventable, risk for recurrence.”

Source:

Figura N,  Flampouri S, Mendenhall NP, et al. Adv Radiat Oncol. 2017;1-16.

Rivaroxaban (Xarelto)

WASHINGTON, DC—Results of the EINSTEIN CHOICE study suggest rivaroxaban is more effective than, and just as safe as, aspirin for long-term anticoagulation in patients with venous thromboembolism (VTE).

In this phase 3 study, patients who had completed 6 to 12 months of anticoagulant therapy were randomized to receive rivaroxaban or aspirin.

Those who received rivaroxaban had a significantly lower risk of recurrent VTE, and the rates of major bleeding were similar between the treatment arms.

“How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding,” said study investigator Philip S. Wells, MD, of The Ottawa Hospital in Ontario, Canada.

“With EINSTEIN CHOICE, for the first time, we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term.”

These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM. The research was funded by Bayer Pharmaceuticals.

The study enrolled 3365 patients with confirmed deep vein thrombosis or pulmonary embolism who were initially treated with anticoagulant therapy for 6 to 12 months.

Patients who required extended anticoagulation at therapeutic doses were not included in this trial, as the objective was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.

Patients were randomized in a 1:1:1 ratio to receive a prophylactic dose of rivaroxaban (10 mg once daily), a treatment dose of rivaroxaban (20 mg once daily), or aspirin (100 mg once daily) for up to 12 months. Sixty percent of patients completed the full 12 months of treatment.

Efficacy

Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.

The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2%, respectively.

For the primary endpoint, the HR for the comparison between the 20 mg and 10 mg rivaroxaban arms was 1.34 (95% CI, 0.65 to 2.75, P=0.42). However, the researchers noted that the comparison of these 2 arms was not powered for significance.

The researchers also found that rivaroxaban reduced patients’ risk of experiencing one of the following events: recurrent VTE, heart attack, ischemic stroke, systemic embolism, or venous thrombosis in another location.

This endpoint occurred in 1.9% of patients in the 10 mg rivaroxaban group (HR=0.33; 95% CI, 0.20 to 0.54; P<0.001), 2.0% of patients in the 20 mg rivaroxaban group (HR=0.35; 95% CI, 0.22 to 0.57; P<0.001), and 5.6% of patients in the aspirin group.

Recurrent VTE or all-cause mortality occurred in 1.3% of patients in the 10 mg rivaroxaban group (HR=0.27; 95% CI, 0.15 to 0.47; P<0.001), 2.1% of patients in the 20 mg rivaroxaban group (HR=0.42; 95% CI, 0.26 to 0.68; P<0.001), and 4.9% of patients in the aspirin group.

Safety

The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.

The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.

Rates of clinically relevant non-major bleeding were 2.0%, 2.7%, and 1.8%, respectively (no significant difference).

“We know from previous studies that only about 40% of venous thromboembolism patients are actually on long-term blood thinners,” Dr Wells said.

“We hope that this study, which shows the blood thinner rivaroxaban is as safe as aspirin but much more effective at preventing future clots, will convince patients and their physicians to continue life-long medication that can prevent potentially dangerous blood clots.”

Rivaroxaban (Xarelto)

WASHINGTON, DC—Results of the EINSTEIN CHOICE study suggest rivaroxaban is more effective than, and just as safe as, aspirin for long-term anticoagulation in patients with venous thromboembolism (VTE).

In this phase 3 study, patients who had completed 6 to 12 months of anticoagulant therapy were randomized to receive rivaroxaban or aspirin.

Those who received rivaroxaban had a significantly lower risk of recurrent VTE, and the rates of major bleeding were similar between the treatment arms.

“How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding,” said study investigator Philip S. Wells, MD, of The Ottawa Hospital in Ontario, Canada.

“With EINSTEIN CHOICE, for the first time, we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term.”

These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM. The research was funded by Bayer Pharmaceuticals.

The study enrolled 3365 patients with confirmed deep vein thrombosis or pulmonary embolism who were initially treated with anticoagulant therapy for 6 to 12 months.

Patients who required extended anticoagulation at therapeutic doses were not included in this trial, as the objective was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.

Patients were randomized in a 1:1:1 ratio to receive a prophylactic dose of rivaroxaban (10 mg once daily), a treatment dose of rivaroxaban (20 mg once daily), or aspirin (100 mg once daily) for up to 12 months. Sixty percent of patients completed the full 12 months of treatment.

Efficacy

Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.

The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2%, respectively.

For the primary endpoint, the HR for the comparison between the 20 mg and 10 mg rivaroxaban arms was 1.34 (95% CI, 0.65 to 2.75, P=0.42). However, the researchers noted that the comparison of these 2 arms was not powered for significance.

The researchers also found that rivaroxaban reduced patients’ risk of experiencing one of the following events: recurrent VTE, heart attack, ischemic stroke, systemic embolism, or venous thrombosis in another location.

This endpoint occurred in 1.9% of patients in the 10 mg rivaroxaban group (HR=0.33; 95% CI, 0.20 to 0.54; P<0.001), 2.0% of patients in the 20 mg rivaroxaban group (HR=0.35; 95% CI, 0.22 to 0.57; P<0.001), and 5.6% of patients in the aspirin group.

Recurrent VTE or all-cause mortality occurred in 1.3% of patients in the 10 mg rivaroxaban group (HR=0.27; 95% CI, 0.15 to 0.47; P<0.001), 2.1% of patients in the 20 mg rivaroxaban group (HR=0.42; 95% CI, 0.26 to 0.68; P<0.001), and 4.9% of patients in the aspirin group.

Safety

The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.

The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.

Rates of clinically relevant non-major bleeding were 2.0%, 2.7%, and 1.8%, respectively (no significant difference).

“We know from previous studies that only about 40% of venous thromboembolism patients are actually on long-term blood thinners,” Dr Wells said.

“We hope that this study, which shows the blood thinner rivaroxaban is as safe as aspirin but much more effective at preventing future clots, will convince patients and their physicians to continue life-long medication that can prevent potentially dangerous blood clots.”

Rivaroxaban (Xarelto)

WASHINGTON, DC—Results of the EINSTEIN CHOICE study suggest rivaroxaban is more effective than, and just as safe as, aspirin for long-term anticoagulation in patients with venous thromboembolism (VTE).

In this phase 3 study, patients who had completed 6 to 12 months of anticoagulant therapy were randomized to receive rivaroxaban or aspirin.

Those who received rivaroxaban had a significantly lower risk of recurrent VTE, and the rates of major bleeding were similar between the treatment arms.

“How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding,” said study investigator Philip S. Wells, MD, of The Ottawa Hospital in Ontario, Canada.

“With EINSTEIN CHOICE, for the first time, we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term.”

These results were presented at the American College of Cardiology’s 66th Annual Scientific Session and published in NEJM. The research was funded by Bayer Pharmaceuticals.

The study enrolled 3365 patients with confirmed deep vein thrombosis or pulmonary embolism who were initially treated with anticoagulant therapy for 6 to 12 months.

Patients who required extended anticoagulation at therapeutic doses were not included in this trial, as the objective was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.

Patients were randomized in a 1:1:1 ratio to receive a prophylactic dose of rivaroxaban (10 mg once daily), a treatment dose of rivaroxaban (20 mg once daily), or aspirin (100 mg once daily) for up to 12 months. Sixty percent of patients completed the full 12 months of treatment.

Efficacy

Both rivaroxaban doses were superior to aspirin in preventing fatal or non-fatal recurrent VTE, the study’s primary efficacy endpoint.

The rate of recurrent VTE was 1.2% in the 10 mg rivaroxaban arm (hazard ratio [HR]=0.26; 95% CI, 0.14 to 0.47; P<0.001), 1.5% in the 20 mg rivaroxaban arm (HR=0.34; 95% CI, 0.20 to 0.59; P<0.001), and 4.4% in the aspirin arm. Fatal VTE occurred in 0%, 0.2%, and 0.2%, respectively.

For the primary endpoint, the HR for the comparison between the 20 mg and 10 mg rivaroxaban arms was 1.34 (95% CI, 0.65 to 2.75, P=0.42). However, the researchers noted that the comparison of these 2 arms was not powered for significance.

The researchers also found that rivaroxaban reduced patients’ risk of experiencing one of the following events: recurrent VTE, heart attack, ischemic stroke, systemic embolism, or venous thrombosis in another location.

This endpoint occurred in 1.9% of patients in the 10 mg rivaroxaban group (HR=0.33; 95% CI, 0.20 to 0.54; P<0.001), 2.0% of patients in the 20 mg rivaroxaban group (HR=0.35; 95% CI, 0.22 to 0.57; P<0.001), and 5.6% of patients in the aspirin group.

Recurrent VTE or all-cause mortality occurred in 1.3% of patients in the 10 mg rivaroxaban group (HR=0.27; 95% CI, 0.15 to 0.47; P<0.001), 2.1% of patients in the 20 mg rivaroxaban group (HR=0.42; 95% CI, 0.26 to 0.68; P<0.001), and 4.9% of patients in the aspirin group.

Safety

The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis.

The rate of major bleeding was 0.4% for the 10 mg rivaroxaban group (HR=1.64; 95% CI, 0.39 to 6.84; P=0.50), 0.5% for the 20 mg rivaroxaban group (HR=2.01; 95% CI, 0.50 to 8.04; P=0.32), and 0.3% for the aspirin group.

Rates of clinically relevant non-major bleeding were 2.0%, 2.7%, and 1.8%, respectively (no significant difference).

“We know from previous studies that only about 40% of venous thromboembolism patients are actually on long-term blood thinners,” Dr Wells said.

“We hope that this study, which shows the blood thinner rivaroxaban is as safe as aspirin but much more effective at preventing future clots, will convince patients and their physicians to continue life-long medication that can prevent potentially dangerous blood clots.”

Hospital Medical Center

Researchers say they have identified 2 signaling proteins that enable resistance to tyrosine kinase inhibitors (TKIs) and could be therapeutic targets for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).

The team found that by deleting these proteins—c-Fos and Dusp1—they could eradicate BCR-ABL-induced B-cell ALL in mice.

And treatment combining c-Fos and Dusp1 inhibitors with the TKI imatinib was able to cure mice with BCR-ABL-driven CML.

The researchers reported these findings in Nature Medicine.

“We think that, within the next 5 years, our data will change the way people think about cancer development and targeted therapy,” said study author Mohammad Azam, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This study identifies a potential Achilles’ heel of kinase-driven cancers, and what we propose is intended to be curative, not just treatment.”

The potential Achilles’ heel is a common point of passage in cells—a signaling node—that appears to be required to generate cancer cells. The node is formed by the signaling proteins c-Fos and Dusp1, according to the researchers.

The team identified c-Fos and Dusp1 by conducting global gene-expression analysis of mouse leukemia cells and human CML cells. Analysis of the human cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive, TKI-resistant cells.

Dr Azam and his colleagues found that signaling from tyrosine kinase and growth factor proteins that support cell expansion (such as IL-3 and IL-6) converge to elevate c-Fos and Dusp1 levels in leukemia cells.

Working together, these molecules maintain the survival of leukemia stem cells (LSCs), which translates to minimal residual disease (MRD) after treatment.

Dr Azam said Dusp1 and c-Fos support the survival of LSCs by increasing the toxic threshold needed to kill them. This means imatinib and other TKIs cannot eliminate the residual LSCs.

After describing the roles of c-Fos and Dusp1, Dr Azam and his colleagues put their ideas to the test in mouse models of CML.

The team tested several treatments in these mice, including:

• monotherapy with imatinib
• inhibitors of c-Fos and Dusp1
• treatment with imatinib and inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression, but mice ultimately relapsed.

Treatment with c-Fos and Dusp1 inhibitors significantly slowed CML progression and prolonged survival in a majority of mice, but this treatment wasn’t curative.

However, a month of treatment with c-Fos and Dusp1 inhibitors as well as imatinib cured about 90% of mice with CML, and there were no signs of MRD.

The researchers also found that simply deleting c-Fos and Dusp1 was sufficient to block the development of B-cell ALL in mice.

The team said they are following up this study by testing c-Fos and Dusp1 as treatment targets for different kinase-fueled cancers.

Hospital Medical Center

Researchers say they have identified 2 signaling proteins that enable resistance to tyrosine kinase inhibitors (TKIs) and could be therapeutic targets for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).

The team found that by deleting these proteins—c-Fos and Dusp1—they could eradicate BCR-ABL-induced B-cell ALL in mice.

And treatment combining c-Fos and Dusp1 inhibitors with the TKI imatinib was able to cure mice with BCR-ABL-driven CML.

The researchers reported these findings in Nature Medicine.

“We think that, within the next 5 years, our data will change the way people think about cancer development and targeted therapy,” said study author Mohammad Azam, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This study identifies a potential Achilles’ heel of kinase-driven cancers, and what we propose is intended to be curative, not just treatment.”

The potential Achilles’ heel is a common point of passage in cells—a signaling node—that appears to be required to generate cancer cells. The node is formed by the signaling proteins c-Fos and Dusp1, according to the researchers.

The team identified c-Fos and Dusp1 by conducting global gene-expression analysis of mouse leukemia cells and human CML cells. Analysis of the human cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive, TKI-resistant cells.

Dr Azam and his colleagues found that signaling from tyrosine kinase and growth factor proteins that support cell expansion (such as IL-3 and IL-6) converge to elevate c-Fos and Dusp1 levels in leukemia cells.

Working together, these molecules maintain the survival of leukemia stem cells (LSCs), which translates to minimal residual disease (MRD) after treatment.

Dr Azam said Dusp1 and c-Fos support the survival of LSCs by increasing the toxic threshold needed to kill them. This means imatinib and other TKIs cannot eliminate the residual LSCs.

After describing the roles of c-Fos and Dusp1, Dr Azam and his colleagues put their ideas to the test in mouse models of CML.

The team tested several treatments in these mice, including:

• monotherapy with imatinib
• inhibitors of c-Fos and Dusp1
• treatment with imatinib and inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression, but mice ultimately relapsed.

Treatment with c-Fos and Dusp1 inhibitors significantly slowed CML progression and prolonged survival in a majority of mice, but this treatment wasn’t curative.

However, a month of treatment with c-Fos and Dusp1 inhibitors as well as imatinib cured about 90% of mice with CML, and there were no signs of MRD.

The researchers also found that simply deleting c-Fos and Dusp1 was sufficient to block the development of B-cell ALL in mice.

The team said they are following up this study by testing c-Fos and Dusp1 as treatment targets for different kinase-fueled cancers.

Hospital Medical Center

Researchers say they have identified 2 signaling proteins that enable resistance to tyrosine kinase inhibitors (TKIs) and could be therapeutic targets for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).

The team found that by deleting these proteins—c-Fos and Dusp1—they could eradicate BCR-ABL-induced B-cell ALL in mice.

And treatment combining c-Fos and Dusp1 inhibitors with the TKI imatinib was able to cure mice with BCR-ABL-driven CML.

The researchers reported these findings in Nature Medicine.

“We think that, within the next 5 years, our data will change the way people think about cancer development and targeted therapy,” said study author Mohammad Azam, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

“This study identifies a potential Achilles’ heel of kinase-driven cancers, and what we propose is intended to be curative, not just treatment.”

The potential Achilles’ heel is a common point of passage in cells—a signaling node—that appears to be required to generate cancer cells. The node is formed by the signaling proteins c-Fos and Dusp1, according to the researchers.

The team identified c-Fos and Dusp1 by conducting global gene-expression analysis of mouse leukemia cells and human CML cells. Analysis of the human cells revealed extremely high levels of c-FOS and DUSP1 in BCR-ABL-positive, TKI-resistant cells.

Dr Azam and his colleagues found that signaling from tyrosine kinase and growth factor proteins that support cell expansion (such as IL-3 and IL-6) converge to elevate c-Fos and Dusp1 levels in leukemia cells.

Working together, these molecules maintain the survival of leukemia stem cells (LSCs), which translates to minimal residual disease (MRD) after treatment.

Dr Azam said Dusp1 and c-Fos support the survival of LSCs by increasing the toxic threshold needed to kill them. This means imatinib and other TKIs cannot eliminate the residual LSCs.

After describing the roles of c-Fos and Dusp1, Dr Azam and his colleagues put their ideas to the test in mouse models of CML.

The team tested several treatments in these mice, including:

• monotherapy with imatinib
• inhibitors of c-Fos and Dusp1
• treatment with imatinib and inhibitors of c-Fos and Dusp1.

As suspected, treatment with imatinib alone initially stopped CML progression, but mice ultimately relapsed.

Treatment with c-Fos and Dusp1 inhibitors significantly slowed CML progression and prolonged survival in a majority of mice, but this treatment wasn’t curative.

However, a month of treatment with c-Fos and Dusp1 inhibitors as well as imatinib cured about 90% of mice with CML, and there were no signs of MRD.

The researchers also found that simply deleting c-Fos and Dusp1 was sufficient to block the development of B-cell ALL in mice.

The team said they are following up this study by testing c-Fos and Dusp1 as treatment targets for different kinase-fueled cancers.

Photo from David Levy

Physicians have reported what they believe is the first case of an allogeneic hematopoietic stem cell transplant (allo-HSCT) curing an adult with congenital dyserythropoietic anemia (CDA).

The patient, David Levy, was previously transfusion-dependent and suffered from iron overload, severe pain, and other adverse effects of his illness.

Levy was denied a transplant for years, but, in 2014, he received a non-myeloablative allo-HSCT from a matched, unrelated donor.

Now, Levy no longer requires transfusions, iron chelation, or immunosuppression, and says he is able to live a normal life.

Damiano Rondelli, MD, of the University of Illinois at Chicago, and his colleagues described Levy’s case in a letter to Bone Marrow Transplantation.

Levy was diagnosed with CDA at 4 months of age and was treated with regular blood transfusions for most of his life. He was 24 when the pain from his illness became so severe that he had to withdraw from graduate school.

“I spent the following years doing nothing—no work, no school, no social contact—because all I could focus on was managing my pain and getting my health back on track,” Levy said.

By age 32, Levy required transfusions every 2 to 3 weeks, had undergone a splenectomy, had an enlarged liver, and was suffering from fatigue, heart palpitations, and iron overload.

“It was bad,” Levy said. “I had been through enough pain. I was angry and depressed, and I wanted a cure. That’s why I started emailing Dr Rondelli.”

Dr Rondelli said that because of Levy’s range of illnesses and inability to tolerate chemotherapy and radiation, several institutions had denied him the possibility of a transplant.

However, Dr Rondelli and his colleagues had reported success with chemotherapy-free allo-HSCT in patients with sickle cell disease. So Dr Rondelli performed Levy’s transplant in 2014.

Levy received a peripheral blood stem cell transplant from an unrelated donor who was a 10/10 HLA match but ABO incompatible. He received conditioning with rabbit anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation.

Levy also received graft-vs-host disease (GVHD) prophylaxis consisting of high-dose cyclophosphamide, mycophenolate mofetil, and sirolimus. And he received standard antibacterial, antifungal, antiviral, and anti-Pneumocystis jiroveci prophylaxis.

Levy experienced platelet engraftment on day 20 and neutrophil engraftment on day 21. Whole-blood donor-cell chimerism was 98.7% on day 30 and 100% on day 60 and beyond.

Levy did develop transient hemolytic anemia due to the ABO incompatibility. He was given a total of 10 units of packed red blood cells until day 78.

Levy was tapered off all immunosuppression at 12 months and has shown no signs of acute or chronic GVHD.

At 24 months after HSCT, Levy’s hemoglobin was 13.7 g/dL, and his ferritin was 376 ng/mL. He has had no iron chelation since the transplant.

“The transplant was hard, and I had some complications, but I am back to normal now,” said Levy, who is now 35.

“I still have some pain and some lingering issues from the years my condition was not properly managed, but I can be independent now. That is the most important thing to me.”

Levy is finishing his doctorate in psychology and running group therapy sessions at a behavioral health hospital.

Dr Rondelli said the potential of this treatment approach is promising.

“The use of this transplant protocol may represent a safe therapeutic strategy to treat adult patients with many types of congenital anemias—perhaps the only possible cure,” he said.

“For many adult patients with a blood disorder, treatment options have been limited because they are often not sick enough to qualify for a risky procedure, or they are too sick to tolerate the toxic drugs used alongside a standard transplant. This procedure gives some adults the option of a stem cell transplant, which was not previously available.”

Photo from David Levy

Physicians have reported what they believe is the first case of an allogeneic hematopoietic stem cell transplant (allo-HSCT) curing an adult with congenital dyserythropoietic anemia (CDA).

The patient, David Levy, was previously transfusion-dependent and suffered from iron overload, severe pain, and other adverse effects of his illness.

Levy was denied a transplant for years, but, in 2014, he received a non-myeloablative allo-HSCT from a matched, unrelated donor.

Now, Levy no longer requires transfusions, iron chelation, or immunosuppression, and says he is able to live a normal life.

Damiano Rondelli, MD, of the University of Illinois at Chicago, and his colleagues described Levy’s case in a letter to Bone Marrow Transplantation.

Levy was diagnosed with CDA at 4 months of age and was treated with regular blood transfusions for most of his life. He was 24 when the pain from his illness became so severe that he had to withdraw from graduate school.

“I spent the following years doing nothing—no work, no school, no social contact—because all I could focus on was managing my pain and getting my health back on track,” Levy said.

By age 32, Levy required transfusions every 2 to 3 weeks, had undergone a splenectomy, had an enlarged liver, and was suffering from fatigue, heart palpitations, and iron overload.

“It was bad,” Levy said. “I had been through enough pain. I was angry and depressed, and I wanted a cure. That’s why I started emailing Dr Rondelli.”

Dr Rondelli said that because of Levy’s range of illnesses and inability to tolerate chemotherapy and radiation, several institutions had denied him the possibility of a transplant.

However, Dr Rondelli and his colleagues had reported success with chemotherapy-free allo-HSCT in patients with sickle cell disease. So Dr Rondelli performed Levy’s transplant in 2014.

Levy received a peripheral blood stem cell transplant from an unrelated donor who was a 10/10 HLA match but ABO incompatible. He received conditioning with rabbit anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation.

Levy also received graft-vs-host disease (GVHD) prophylaxis consisting of high-dose cyclophosphamide, mycophenolate mofetil, and sirolimus. And he received standard antibacterial, antifungal, antiviral, and anti-Pneumocystis jiroveci prophylaxis.

Levy experienced platelet engraftment on day 20 and neutrophil engraftment on day 21. Whole-blood donor-cell chimerism was 98.7% on day 30 and 100% on day 60 and beyond.

Levy did develop transient hemolytic anemia due to the ABO incompatibility. He was given a total of 10 units of packed red blood cells until day 78.

Levy was tapered off all immunosuppression at 12 months and has shown no signs of acute or chronic GVHD.

At 24 months after HSCT, Levy’s hemoglobin was 13.7 g/dL, and his ferritin was 376 ng/mL. He has had no iron chelation since the transplant.

“The transplant was hard, and I had some complications, but I am back to normal now,” said Levy, who is now 35.

“I still have some pain and some lingering issues from the years my condition was not properly managed, but I can be independent now. That is the most important thing to me.”

Levy is finishing his doctorate in psychology and running group therapy sessions at a behavioral health hospital.

Dr Rondelli said the potential of this treatment approach is promising.

“The use of this transplant protocol may represent a safe therapeutic strategy to treat adult patients with many types of congenital anemias—perhaps the only possible cure,” he said.

“For many adult patients with a blood disorder, treatment options have been limited because they are often not sick enough to qualify for a risky procedure, or they are too sick to tolerate the toxic drugs used alongside a standard transplant. This procedure gives some adults the option of a stem cell transplant, which was not previously available.”

Photo from David Levy

Physicians have reported what they believe is the first case of an allogeneic hematopoietic stem cell transplant (allo-HSCT) curing an adult with congenital dyserythropoietic anemia (CDA).

The patient, David Levy, was previously transfusion-dependent and suffered from iron overload, severe pain, and other adverse effects of his illness.

Levy was denied a transplant for years, but, in 2014, he received a non-myeloablative allo-HSCT from a matched, unrelated donor.

Now, Levy no longer requires transfusions, iron chelation, or immunosuppression, and says he is able to live a normal life.

Damiano Rondelli, MD, of the University of Illinois at Chicago, and his colleagues described Levy’s case in a letter to Bone Marrow Transplantation.

Levy was diagnosed with CDA at 4 months of age and was treated with regular blood transfusions for most of his life. He was 24 when the pain from his illness became so severe that he had to withdraw from graduate school.

“I spent the following years doing nothing—no work, no school, no social contact—because all I could focus on was managing my pain and getting my health back on track,” Levy said.

By age 32, Levy required transfusions every 2 to 3 weeks, had undergone a splenectomy, had an enlarged liver, and was suffering from fatigue, heart palpitations, and iron overload.

“It was bad,” Levy said. “I had been through enough pain. I was angry and depressed, and I wanted a cure. That’s why I started emailing Dr Rondelli.”

Dr Rondelli said that because of Levy’s range of illnesses and inability to tolerate chemotherapy and radiation, several institutions had denied him the possibility of a transplant.

However, Dr Rondelli and his colleagues had reported success with chemotherapy-free allo-HSCT in patients with sickle cell disease. So Dr Rondelli performed Levy’s transplant in 2014.

Levy received a peripheral blood stem cell transplant from an unrelated donor who was a 10/10 HLA match but ABO incompatible. He received conditioning with rabbit anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation.

Levy also received graft-vs-host disease (GVHD) prophylaxis consisting of high-dose cyclophosphamide, mycophenolate mofetil, and sirolimus. And he received standard antibacterial, antifungal, antiviral, and anti-Pneumocystis jiroveci prophylaxis.

Levy experienced platelet engraftment on day 20 and neutrophil engraftment on day 21. Whole-blood donor-cell chimerism was 98.7% on day 30 and 100% on day 60 and beyond.

Levy did develop transient hemolytic anemia due to the ABO incompatibility. He was given a total of 10 units of packed red blood cells until day 78.

Levy was tapered off all immunosuppression at 12 months and has shown no signs of acute or chronic GVHD.

At 24 months after HSCT, Levy’s hemoglobin was 13.7 g/dL, and his ferritin was 376 ng/mL. He has had no iron chelation since the transplant.

“The transplant was hard, and I had some complications, but I am back to normal now,” said Levy, who is now 35.

“I still have some pain and some lingering issues from the years my condition was not properly managed, but I can be independent now. That is the most important thing to me.”

Levy is finishing his doctorate in psychology and running group therapy sessions at a behavioral health hospital.

Dr Rondelli said the potential of this treatment approach is promising.

“The use of this transplant protocol may represent a safe therapeutic strategy to treat adult patients with many types of congenital anemias—perhaps the only possible cure,” he said.

“For many adult patients with a blood disorder, treatment options have been limited because they are often not sick enough to qualify for a risky procedure, or they are too sick to tolerate the toxic drugs used alongside a standard transplant. This procedure gives some adults the option of a stem cell transplant, which was not previously available.”

Image by Spencer Phillips

New research appears to explain how 10q21.2 influences the risk of high-hyperdiploid acute lymphoblastic leukemia (HD-ALL).

Previous research indicated that variation in the gene ARID5B at 10q21.2 is associated with HD-ALL.

Now, researchers have reported that the 10q21.2 risk locus for HD-ALL is mediated through the single nucleotide polymorphism (SNP) rs7090445, which disrupts RUNX3 transcription factor binding.

Specifically, the rs7090445-C allele confers an increased risk of HD-ALL through reduced RUNX3-mediated expression of ARID5B.

The researchers described these findings in Nature Communications.

“This study expands our understanding of how genetic risk factors can influence the development of acute lymphoblastic leukemia . . .,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

Dr Houlston and his colleagues focused this research on 10q21.2 because it had previously been implicated in HD-ALL, but it wasn’t clear how the region affects the risk of HD-ALL.

The team said they found that a SNP in the region, rs7090445, is “highly associated” with HD-ALL.

Further investigation revealed that variation at rs7090445 disrupts RUNX3 binding and reduces the expression of ARID5B, as RUNX3 regulates ARID5B expression.

The researchers also discovered that the rs7090445-C risk allele, which is associated with reduced ARID5B expression, is amplified in HD-ALL. The risk allele is “preferentially retained” on additional copies of chromosome 10 in HD-ALL blasts.

“We implicate reduced expression of a gene called ARID5B in the production and release of the immature ‘blast’ cells that characterize [HD-ALL],” Dr Houlston said. “Our study gives a new insight into the causes of the disease and may open up new strategies for prevention.”

Image by Spencer Phillips

New research appears to explain how 10q21.2 influences the risk of high-hyperdiploid acute lymphoblastic leukemia (HD-ALL).

Previous research indicated that variation in the gene ARID5B at 10q21.2 is associated with HD-ALL.

Now, researchers have reported that the 10q21.2 risk locus for HD-ALL is mediated through the single nucleotide polymorphism (SNP) rs7090445, which disrupts RUNX3 transcription factor binding.

Specifically, the rs7090445-C allele confers an increased risk of HD-ALL through reduced RUNX3-mediated expression of ARID5B.

The researchers described these findings in Nature Communications.

“This study expands our understanding of how genetic risk factors can influence the development of acute lymphoblastic leukemia . . .,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

Dr Houlston and his colleagues focused this research on 10q21.2 because it had previously been implicated in HD-ALL, but it wasn’t clear how the region affects the risk of HD-ALL.

The team said they found that a SNP in the region, rs7090445, is “highly associated” with HD-ALL.

Further investigation revealed that variation at rs7090445 disrupts RUNX3 binding and reduces the expression of ARID5B, as RUNX3 regulates ARID5B expression.

The researchers also discovered that the rs7090445-C risk allele, which is associated with reduced ARID5B expression, is amplified in HD-ALL. The risk allele is “preferentially retained” on additional copies of chromosome 10 in HD-ALL blasts.

“We implicate reduced expression of a gene called ARID5B in the production and release of the immature ‘blast’ cells that characterize [HD-ALL],” Dr Houlston said. “Our study gives a new insight into the causes of the disease and may open up new strategies for prevention.”

Image by Spencer Phillips

New research appears to explain how 10q21.2 influences the risk of high-hyperdiploid acute lymphoblastic leukemia (HD-ALL).

Previous research indicated that variation in the gene ARID5B at 10q21.2 is associated with HD-ALL.

Now, researchers have reported that the 10q21.2 risk locus for HD-ALL is mediated through the single nucleotide polymorphism (SNP) rs7090445, which disrupts RUNX3 transcription factor binding.

Specifically, the rs7090445-C allele confers an increased risk of HD-ALL through reduced RUNX3-mediated expression of ARID5B.

The researchers described these findings in Nature Communications.

“This study expands our understanding of how genetic risk factors can influence the development of acute lymphoblastic leukemia . . .,” said study author Richard Houlston, MD, PhD, of The Institute of Cancer Research in London, UK.

Dr Houlston and his colleagues focused this research on 10q21.2 because it had previously been implicated in HD-ALL, but it wasn’t clear how the region affects the risk of HD-ALL.

The team said they found that a SNP in the region, rs7090445, is “highly associated” with HD-ALL.

Further investigation revealed that variation at rs7090445 disrupts RUNX3 binding and reduces the expression of ARID5B, as RUNX3 regulates ARID5B expression.

The researchers also discovered that the rs7090445-C risk allele, which is associated with reduced ARID5B expression, is amplified in HD-ALL. The risk allele is “preferentially retained” on additional copies of chromosome 10 in HD-ALL blasts.

“We implicate reduced expression of a gene called ARID5B in the production and release of the immature ‘blast’ cells that characterize [HD-ALL],” Dr Houlston said. “Our study gives a new insight into the causes of the disease and may open up new strategies for prevention.”

For patients undergoing elective permanent colostomy, prophylactic augmentation of the abdominal wall using mesh at the ostomy site prevents the development of parastomal hernia, according to a report published in the April issue of Annals of Surgery.

The incidence of parastomal hernia is expected to rise because of the increasing number of cancer patients surviving with a colostomy, and the rising number of obese patients who have increased tension on the abdominal wall because of their elevated intra-abdominal pressure and larger abdominal radius. Researchers in the Netherlands performed a prospective randomized study, the PREVENT trial, to assess whether augmenting the abdominal wall at the ostomy site, using a lightweight mesh, would be safe, feasible, and effective at preventing parastomal hernia. They reported their findings after 1 year of follow-up; the study will continue until longer-term results are available at 5 years.

castillodominici/Thinkstock

This study was supported by Canisius Wilhelmina Hospital’s surgery research fund, the Netherlands Organization for Health Research and Development, and Covidien/Medtronic. Dr. Brandsma and his associates reported having no relevant financial disclosures.

For patients undergoing elective permanent colostomy, prophylactic augmentation of the abdominal wall using mesh at the ostomy site prevents the development of parastomal hernia, according to a report published in the April issue of Annals of Surgery.

The incidence of parastomal hernia is expected to rise because of the increasing number of cancer patients surviving with a colostomy, and the rising number of obese patients who have increased tension on the abdominal wall because of their elevated intra-abdominal pressure and larger abdominal radius. Researchers in the Netherlands performed a prospective randomized study, the PREVENT trial, to assess whether augmenting the abdominal wall at the ostomy site, using a lightweight mesh, would be safe, feasible, and effective at preventing parastomal hernia. They reported their findings after 1 year of follow-up; the study will continue until longer-term results are available at 5 years.

castillodominici/Thinkstock

This study was supported by Canisius Wilhelmina Hospital’s surgery research fund, the Netherlands Organization for Health Research and Development, and Covidien/Medtronic. Dr. Brandsma and his associates reported having no relevant financial disclosures.

For patients undergoing elective permanent colostomy, prophylactic augmentation of the abdominal wall using mesh at the ostomy site prevents the development of parastomal hernia, according to a report published in the April issue of Annals of Surgery.

The incidence of parastomal hernia is expected to rise because of the increasing number of cancer patients surviving with a colostomy, and the rising number of obese patients who have increased tension on the abdominal wall because of their elevated intra-abdominal pressure and larger abdominal radius. Researchers in the Netherlands performed a prospective randomized study, the PREVENT trial, to assess whether augmenting the abdominal wall at the ostomy site, using a lightweight mesh, would be safe, feasible, and effective at preventing parastomal hernia. They reported their findings after 1 year of follow-up; the study will continue until longer-term results are available at 5 years.

castillodominici/Thinkstock

This study was supported by Canisius Wilhelmina Hospital’s surgery research fund, the Netherlands Organization for Health Research and Development, and Covidien/Medtronic. Dr. Brandsma and his associates reported having no relevant financial disclosures.

FROM SEMINARS IN ARTHRITIS & RHEUMATISM

Around two-thirds of patients with severe or refractory sarcoidosis show a significant clinical response to tumor necrosis factor (TNF) antagonists, according to findings from a retrospective, multicenter cohort study.

Biologic agents targeting TNF, such as etanercept, infliximab, and adalimumab, have been introduced as a third-line option for patients with disease that is refractory to other treatments. However, Yvan Jamilloux, MD, of the Hospices Civils de Lyon (France) and his coauthors reported that there are still insufficient data available on efficacy and safety of these drugs in the context of sarcoidosis.

Dr. Jamilloux and his colleagues analyzed data from 132 sarcoidosis patients who received TNF antagonists, 122 (92%) of whom had severe sarcoidosis (Semin Arthritis Rheum. 2017 Mar 8. doi: 10.1016/j.semarthrit.2017.03.005).

Overall, 64% of patients showed clinical improvements in response to TNF antagonists; 18% had a complete response, and 46% had a partial response. However, 33 (25%) patients showed no change, and 14 (11%) had continued disease progression despite treatment with TNF antagonists. In another 16 patients who received a second TNF antagonist, 10 (63%) had a complete or partial clinical response. The investigators could find no differences in response between anti-TNF agents or between monotherapy and a combination with an immunosuppressant.

Pulmonary involvement was associated with a significantly lower clinical response, but none of the other factors examined in a multivariate analysis (sex, age, ethnicity, organ involvement, disease duration, steroid dosage, or prior immunosuppressant use) distinguished responders and nonresponders.

The authors noted that these response rates were lower than those seen in the literature and suggested this may be attributable to the multicenter design, more patients with longer-lasting and more refractory disease, and longer times under biologic therapy (median 12 months).

The researchers reported significant improvements in central nervous system, peripheral nervous system, heart, skin, and upper respiratory tract involvements based on declines in Extrapulmonary Physician Organ Severity Tool (ePOST) scores. There were also improvements in the eye, muscle, and lung, but these were not statistically significant.

TNF-antagonist therapy was associated with a high rate of adverse events. Around half of all patients (52%) experienced adverse events, such as pneumonia, urinary tract infections, bacterial sepsis, and herpes zoster. In 31 patients (23%), these led to treatment cessation.

Nine patients also had severe allergic reactions, four had paradoxical granulomatous reactions, three developed neutralizing antibodies against anti-TNF agents, two patients had demyelinating lesions, and one had a serum sickness-like reaction. All of these events led to discontinuation.

Overall, 128 (97%) of the patients in the study had received corticosteroids as first-line therapy, and 125 (95%) had received at least one second-line immunosuppressive drug over a median duration of 16 months. Most were treated with infliximab (91%) as the first-line TNF antagonist, followed by adalimumab (6%), etanercept (2%), and certolizumab pegol (1%).

Treatment with TNF antagonists was associated with significant reductions in corticosteroid use; the mean daily prednisone dose decreased from 23 mg/day to 11 mg/day over the median 20.5-month follow-up. This was seen even in the 33 patients who showed no change in their disease course after TNF-antagonist therapy.

No conflicts of interest were declared.

rhnews@frontlinemedcom.com

FROM SEMINARS IN ARTHRITIS & RHEUMATISM

Around two-thirds of patients with severe or refractory sarcoidosis show a significant clinical response to tumor necrosis factor (TNF) antagonists, according to findings from a retrospective, multicenter cohort study.

Biologic agents targeting TNF, such as etanercept, infliximab, and adalimumab, have been introduced as a third-line option for patients with disease that is refractory to other treatments. However, Yvan Jamilloux, MD, of the Hospices Civils de Lyon (France) and his coauthors reported that there are still insufficient data available on efficacy and safety of these drugs in the context of sarcoidosis.

Dr. Jamilloux and his colleagues analyzed data from 132 sarcoidosis patients who received TNF antagonists, 122 (92%) of whom had severe sarcoidosis (Semin Arthritis Rheum. 2017 Mar 8. doi: 10.1016/j.semarthrit.2017.03.005).

Overall, 64% of patients showed clinical improvements in response to TNF antagonists; 18% had a complete response, and 46% had a partial response. However, 33 (25%) patients showed no change, and 14 (11%) had continued disease progression despite treatment with TNF antagonists. In another 16 patients who received a second TNF antagonist, 10 (63%) had a complete or partial clinical response. The investigators could find no differences in response between anti-TNF agents or between monotherapy and a combination with an immunosuppressant.

Pulmonary involvement was associated with a significantly lower clinical response, but none of the other factors examined in a multivariate analysis (sex, age, ethnicity, organ involvement, disease duration, steroid dosage, or prior immunosuppressant use) distinguished responders and nonresponders.

The authors noted that these response rates were lower than those seen in the literature and suggested this may be attributable to the multicenter design, more patients with longer-lasting and more refractory disease, and longer times under biologic therapy (median 12 months).

The researchers reported significant improvements in central nervous system, peripheral nervous system, heart, skin, and upper respiratory tract involvements based on declines in Extrapulmonary Physician Organ Severity Tool (ePOST) scores. There were also improvements in the eye, muscle, and lung, but these were not statistically significant.

TNF-antagonist therapy was associated with a high rate of adverse events. Around half of all patients (52%) experienced adverse events, such as pneumonia, urinary tract infections, bacterial sepsis, and herpes zoster. In 31 patients (23%), these led to treatment cessation.

Nine patients also had severe allergic reactions, four had paradoxical granulomatous reactions, three developed neutralizing antibodies against anti-TNF agents, two patients had demyelinating lesions, and one had a serum sickness-like reaction. All of these events led to discontinuation.

Overall, 128 (97%) of the patients in the study had received corticosteroids as first-line therapy, and 125 (95%) had received at least one second-line immunosuppressive drug over a median duration of 16 months. Most were treated with infliximab (91%) as the first-line TNF antagonist, followed by adalimumab (6%), etanercept (2%), and certolizumab pegol (1%).

Treatment with TNF antagonists was associated with significant reductions in corticosteroid use; the mean daily prednisone dose decreased from 23 mg/day to 11 mg/day over the median 20.5-month follow-up. This was seen even in the 33 patients who showed no change in their disease course after TNF-antagonist therapy.

No conflicts of interest were declared.

rhnews@frontlinemedcom.com

FROM SEMINARS IN ARTHRITIS & RHEUMATISM

Around two-thirds of patients with severe or refractory sarcoidosis show a significant clinical response to tumor necrosis factor (TNF) antagonists, according to findings from a retrospective, multicenter cohort study.

Biologic agents targeting TNF, such as etanercept, infliximab, and adalimumab, have been introduced as a third-line option for patients with disease that is refractory to other treatments. However, Yvan Jamilloux, MD, of the Hospices Civils de Lyon (France) and his coauthors reported that there are still insufficient data available on efficacy and safety of these drugs in the context of sarcoidosis.

Dr. Jamilloux and his colleagues analyzed data from 132 sarcoidosis patients who received TNF antagonists, 122 (92%) of whom had severe sarcoidosis (Semin Arthritis Rheum. 2017 Mar 8. doi: 10.1016/j.semarthrit.2017.03.005).

Overall, 64% of patients showed clinical improvements in response to TNF antagonists; 18% had a complete response, and 46% had a partial response. However, 33 (25%) patients showed no change, and 14 (11%) had continued disease progression despite treatment with TNF antagonists. In another 16 patients who received a second TNF antagonist, 10 (63%) had a complete or partial clinical response. The investigators could find no differences in response between anti-TNF agents or between monotherapy and a combination with an immunosuppressant.

Pulmonary involvement was associated with a significantly lower clinical response, but none of the other factors examined in a multivariate analysis (sex, age, ethnicity, organ involvement, disease duration, steroid dosage, or prior immunosuppressant use) distinguished responders and nonresponders.

The authors noted that these response rates were lower than those seen in the literature and suggested this may be attributable to the multicenter design, more patients with longer-lasting and more refractory disease, and longer times under biologic therapy (median 12 months).

The researchers reported significant improvements in central nervous system, peripheral nervous system, heart, skin, and upper respiratory tract involvements based on declines in Extrapulmonary Physician Organ Severity Tool (ePOST) scores. There were also improvements in the eye, muscle, and lung, but these were not statistically significant.

TNF-antagonist therapy was associated with a high rate of adverse events. Around half of all patients (52%) experienced adverse events, such as pneumonia, urinary tract infections, bacterial sepsis, and herpes zoster. In 31 patients (23%), these led to treatment cessation.

Nine patients also had severe allergic reactions, four had paradoxical granulomatous reactions, three developed neutralizing antibodies against anti-TNF agents, two patients had demyelinating lesions, and one had a serum sickness-like reaction. All of these events led to discontinuation.

Overall, 128 (97%) of the patients in the study had received corticosteroids as first-line therapy, and 125 (95%) had received at least one second-line immunosuppressive drug over a median duration of 16 months. Most were treated with infliximab (91%) as the first-line TNF antagonist, followed by adalimumab (6%), etanercept (2%), and certolizumab pegol (1%).

Treatment with TNF antagonists was associated with significant reductions in corticosteroid use; the mean daily prednisone dose decreased from 23 mg/day to 11 mg/day over the median 20.5-month follow-up. This was seen even in the 33 patients who showed no change in their disease course after TNF-antagonist therapy.

No conflicts of interest were declared.

rhnews@frontlinemedcom.com

Global cases of HIV from 2015 to 2035 would be reduced by over 50% if the Joint United Nations Program on HIV/AIDS 95/95/95 target is met and a moderately effective HIV vaccine is introduced by 2020, according to new research published in Proceedings of the National Academy of Sciences.

A custom model based on current rates of diagnosis and treatment in 127 countries predicts that a total of 49 million new cases of HIV would occur globally from 2015 to 2035, investigators said. Achieving the UNAIDS goal of 95% disease diagnosis, 95% antiretroviral coverage, and 95% viral suppression by 2030 would avert 25 million cases by 2035. Achieving the more modest 90/90/90 target would avert 22 million cases within the same time period.

grandeduc/Thinkstock

lfranki@frontlinemedcom.com

On Twitter @IDPractitioner

Global cases of HIV from 2015 to 2035 would be reduced by over 50% if the Joint United Nations Program on HIV/AIDS 95/95/95 target is met and a moderately effective HIV vaccine is introduced by 2020, according to new research published in Proceedings of the National Academy of Sciences.

A custom model based on current rates of diagnosis and treatment in 127 countries predicts that a total of 49 million new cases of HIV would occur globally from 2015 to 2035, investigators said. Achieving the UNAIDS goal of 95% disease diagnosis, 95% antiretroviral coverage, and 95% viral suppression by 2030 would avert 25 million cases by 2035. Achieving the more modest 90/90/90 target would avert 22 million cases within the same time period.

grandeduc/Thinkstock

lfranki@frontlinemedcom.com

On Twitter @IDPractitioner

Global cases of HIV from 2015 to 2035 would be reduced by over 50% if the Joint United Nations Program on HIV/AIDS 95/95/95 target is met and a moderately effective HIV vaccine is introduced by 2020, according to new research published in Proceedings of the National Academy of Sciences.

A custom model based on current rates of diagnosis and treatment in 127 countries predicts that a total of 49 million new cases of HIV would occur globally from 2015 to 2035, investigators said. Achieving the UNAIDS goal of 95% disease diagnosis, 95% antiretroviral coverage, and 95% viral suppression by 2030 would avert 25 million cases by 2035. Achieving the more modest 90/90/90 target would avert 22 million cases within the same time period.

grandeduc/Thinkstock

lfranki@frontlinemedcom.com

On Twitter @IDPractitioner

To the Editor:
Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway, is useful in the treatment of advanced basal cell carcinomas (BCCs).¹ Common side effects of vismodegib include alopecia (58%), muscle spasms (71%), and dysgeusia (71%).² Some of these side effects have been hypothesized to be mechanism related.^3,4 Keratoacanthomas have been reported to occur after vismodegib treatment of BCC.⁵ We report 3 cases illustrating reversible cutaneous side effects of vismodegib: alopecia, follicular dermatitis, and drug hypersensitivity reaction.

A 53-year-old man with a locally advanced BCC of the right medial canthus began experiencing progressive and diffuse hair loss on the beard area, parietal scalp, eyelashes, and eyebrows after 2 months of vismodegib treatment. At 12 months of treatment, he had complete loss of eyelashes and eyebrows (Figure, A). After vismodegib was discontinued due to disease progression, all of his hair began regrowing within several months, with complete hair regrowth observed at 20 months after the last dose (Figure, B).

A 55-year-old man with several locally advanced BCCs developed new-onset mildly pruritic, acneform lesions on the chest and back after 4 months of vismodegib treatment. Biopsy of the lesions showed a folliculocentric mixed dermal infiltrate. The patient did not have a history of follicular dermatitis. The dermatitis resolved several months after onset without treatment, despite continued vismodegib.

A 55-year-old man with locally advanced BCCs developed erythematous dermal plaques on the arms and chest after 2 months of vismodegib treatment. Lesions were asymptomatic. He was not using any other medications and did not have any contact allergen exposures. Punch biopsy showed superficial and deep perivascular dermatitis with occasional eosinophils, consistent with drug hypersensitivity. Although lesions spontaneously resolved without treatment after 1 month, he experienced a couple more bouts of these lesions over the next year. He continued vismodegib for 2 years without return of this eruption.

The average time frame for hair regrowth after vismodegib cessation has not been characterized and awaits future larger studies. The frequency of follicular dermatitis and drug eruption also has not been determined and may require careful observation by dermatologists in larger numbers of treated patients. 

Because the hedgehog pathway is critical for normal hair follicle function, follicle-based toxicities of vismodegib including alopecia and folliculitis could be hypothesized to reflect effective blockade of the pathway.⁶ Currently, there are no data that these changes correlate with tumor response. 

Although alopecia is a recognized side effect of vismodegib, regrowth has not been previously reported.^1,2 Knowledge of the reversibility of alopecia as well as other toxicities has the potential to influence patient decision-making on drug initiation and adherence.

To the Editor:
Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway, is useful in the treatment of advanced basal cell carcinomas (BCCs).¹ Common side effects of vismodegib include alopecia (58%), muscle spasms (71%), and dysgeusia (71%).² Some of these side effects have been hypothesized to be mechanism related.^3,4 Keratoacanthomas have been reported to occur after vismodegib treatment of BCC.⁵ We report 3 cases illustrating reversible cutaneous side effects of vismodegib: alopecia, follicular dermatitis, and drug hypersensitivity reaction.

A 53-year-old man with a locally advanced BCC of the right medial canthus began experiencing progressive and diffuse hair loss on the beard area, parietal scalp, eyelashes, and eyebrows after 2 months of vismodegib treatment. At 12 months of treatment, he had complete loss of eyelashes and eyebrows (Figure, A). After vismodegib was discontinued due to disease progression, all of his hair began regrowing within several months, with complete hair regrowth observed at 20 months after the last dose (Figure, B).

A 55-year-old man with several locally advanced BCCs developed new-onset mildly pruritic, acneform lesions on the chest and back after 4 months of vismodegib treatment. Biopsy of the lesions showed a folliculocentric mixed dermal infiltrate. The patient did not have a history of follicular dermatitis. The dermatitis resolved several months after onset without treatment, despite continued vismodegib.

A 55-year-old man with locally advanced BCCs developed erythematous dermal plaques on the arms and chest after 2 months of vismodegib treatment. Lesions were asymptomatic. He was not using any other medications and did not have any contact allergen exposures. Punch biopsy showed superficial and deep perivascular dermatitis with occasional eosinophils, consistent with drug hypersensitivity. Although lesions spontaneously resolved without treatment after 1 month, he experienced a couple more bouts of these lesions over the next year. He continued vismodegib for 2 years without return of this eruption.

The average time frame for hair regrowth after vismodegib cessation has not been characterized and awaits future larger studies. The frequency of follicular dermatitis and drug eruption also has not been determined and may require careful observation by dermatologists in larger numbers of treated patients. 

Because the hedgehog pathway is critical for normal hair follicle function, follicle-based toxicities of vismodegib including alopecia and folliculitis could be hypothesized to reflect effective blockade of the pathway.⁶ Currently, there are no data that these changes correlate with tumor response. 

Although alopecia is a recognized side effect of vismodegib, regrowth has not been previously reported.^1,2 Knowledge of the reversibility of alopecia as well as other toxicities has the potential to influence patient decision-making on drug initiation and adherence.

To the Editor:
Vismodegib, a first-in-class inhibitor of the hedgehog signaling pathway, is useful in the treatment of advanced basal cell carcinomas (BCCs).¹ Common side effects of vismodegib include alopecia (58%), muscle spasms (71%), and dysgeusia (71%).² Some of these side effects have been hypothesized to be mechanism related.^3,4 Keratoacanthomas have been reported to occur after vismodegib treatment of BCC.⁵ We report 3 cases illustrating reversible cutaneous side effects of vismodegib: alopecia, follicular dermatitis, and drug hypersensitivity reaction.

A 53-year-old man with a locally advanced BCC of the right medial canthus began experiencing progressive and diffuse hair loss on the beard area, parietal scalp, eyelashes, and eyebrows after 2 months of vismodegib treatment. At 12 months of treatment, he had complete loss of eyelashes and eyebrows (Figure, A). After vismodegib was discontinued due to disease progression, all of his hair began regrowing within several months, with complete hair regrowth observed at 20 months after the last dose (Figure, B).

A 55-year-old man with several locally advanced BCCs developed new-onset mildly pruritic, acneform lesions on the chest and back after 4 months of vismodegib treatment. Biopsy of the lesions showed a folliculocentric mixed dermal infiltrate. The patient did not have a history of follicular dermatitis. The dermatitis resolved several months after onset without treatment, despite continued vismodegib.

A 55-year-old man with locally advanced BCCs developed erythematous dermal plaques on the arms and chest after 2 months of vismodegib treatment. Lesions were asymptomatic. He was not using any other medications and did not have any contact allergen exposures. Punch biopsy showed superficial and deep perivascular dermatitis with occasional eosinophils, consistent with drug hypersensitivity. Although lesions spontaneously resolved without treatment after 1 month, he experienced a couple more bouts of these lesions over the next year. He continued vismodegib for 2 years without return of this eruption.

The average time frame for hair regrowth after vismodegib cessation has not been characterized and awaits future larger studies. The frequency of follicular dermatitis and drug eruption also has not been determined and may require careful observation by dermatologists in larger numbers of treated patients. 

Because the hedgehog pathway is critical for normal hair follicle function, follicle-based toxicities of vismodegib including alopecia and folliculitis could be hypothesized to reflect effective blockade of the pathway.⁶ Currently, there are no data that these changes correlate with tumor response. 

Although alopecia is a recognized side effect of vismodegib, regrowth has not been previously reported.^1,2 Knowledge of the reversibility of alopecia as well as other toxicities has the potential to influence patient decision-making on drug initiation and adherence.