Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Study Overview

Objective. To evaluate the efficacy and safety of the anti-CD19 chimeric antigen receptor (CAR) T-cell, axicabtagene ciloleucel (axi-cel), in patients with refractory large B-cell lymphoma.

Design. The ZUMA-1 trial was a phase 1-2 multicenter study. The results of the primary analysis and updated analysis with 1-year follow up of the phase 2 portion of ZUMA-1 are reported here.

Setting and participants. The phase 2 portion of the ZUMA-1 trial enrolled 111 patients from 22 centers in the United States (21) and Israel (1) from November 2015 through September 2016. Eligible patients included those with histologically confirmed large B-cell lymphoma, primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were required to have refractory disease, defined as disease progression or stable disease as the best response to chemotherapy or disease progression within 12 months following autologous stem cell transplantation. All patients were required to have adequate organ function, an absolute neutrophil count > 1000, absolute lymphocyte count > 100 and platelet count > 75,000.

Intervention. Patients first underwent leukapheresis and CAR T-cell manufacturing. Following this patients were admitted to the hospital and received a low-dose conditioning regimen consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² given on days –5, –4 and –3. On day 0 the patient was infused with their manufactured CAR T-cell product at a target dose of 2 x10⁶ CAR T cells per kilogram of body weight. Patients could not receive “bridging chemotherapy” between leukapheresis and infusion of axi-cel product. Patients could be retreated with axi-cel if they experienced disease progression at least 3 months after their first dose.

Main outcome measures. The primary endpoint of this study was objective response rate, which was defined as the combined rate of complete response (CR) and partial response (PR). The secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and adverse events. Blood levels of CAR T cells and serum cytokine levels were followed.

Main results. A total of 111 patients were enrolled. Axi-cel was administered to 101 patients included in the intention to treat analysis. Of these, 77 had diffuse large B-cell lymphoma and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma. The median follow-up was 8.7 months for the primary analysis and updated analysis median follow-up was 15.4 months. The median time from leukapheresis to delivery of the product was 17 days. Only 1 patient had unsuccessful manufacturing. The median age of the treated patients was 58 years. Most of the patients (77%) had disease resistant to second-line or later therapy and 21% had disease relapse after autologous stem cell transplant.

Primary analysis results. The objective response rate was 82% with a 54% CR rate. The median time to response was 1 month and median duration of response was 8.1 months. The response rates were consistent across all subgroups including age, disease stage, IPI score, presence or absence of bulky disease, cell-of-origin subtype, and the use of tocilizumab or glucocorticoids. High response rates were maintained in those with primary refractory disease (response rate 88%) and those with prior autologous stem cell transplant (response rate 76%). The response rate was not influenced by CD19 expression. At the time of the primary analysis 52 patients died from disease progression and 3 died from adverse events during treatment. Forty-four patients remained in remission, 39 of whom maintained a CR.

Updated analysis results. At the time of the updated analysis 108 patients in the phase 1 and phase 2 portions had been followed for at least 12 months. The objective response rate was 82% with a CR rate of 58%. At the data cut-off, 42% remained in response with 40% maintaining a CR. Again, response rates were consistent across all previously mentioned subgroups. The median duration of response was 11.1 months. The median PFS was 5.8 months with PFS rate of 41% at 15 months. The median OS was not reached. A total of 56% of patients remained alive at the time of this analysis.

Safety. During treatment 100% of patients had adverse events (AEs), which were grade 3 or higher in 95%. Fevers (85%), neutropenia (84%) and anemia (66%) were the most common AEs. Myelosuppression was the most common grade 3 or higher AE. Cytokine release syndrome occurred in 93% of patients of which 13% were grade 3 or higher (9% grade 3, 3% grade 4 and 1% grade 5). 17% of patients required vasopressor support. The median time from infusion to the onset of cytokine release syndrome was 2 days (range, 1–12). The median time to resolution was 8 days. One grade 5 event of hemophagocytic lymphohistiocytosis and one grade 5 cardiac arrest occurred. Grade 3 or higher neurological events occurred in 28% of patients, with encephalopathy occurring in 21%. Neurological events occurred at a median of 5 days after infusion and lasted for a median of 17 days after infusion. Forty-three percent of patients received tocilizumab and 27% received glucocorticoids.

Biomarkers. CAR T levels peaked within 14 days after infusion. Three patients with a CR at 24 months still had detectable levels in the blood. CAR T cell expansion as significantly associated with disease response. Interleukin -6, -10, -15 and -2Ra levels were significantly associated with neurological events and cytokine release syndrome of grade 3 or higher. Anti-CAR antibodies were not detected in any patient.

Commentary

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma with 5-year survival rates of ~60% following conventional chemoimmunotherapy in the first-line setting. Following relapse, salvage therapy followed by high-dose chemotherapy with autologous stem-cell transplantation can result in long-term remissions; however, those who relapse have a poor prognosis. The recently published SCHOLAR-1 study retrospectively analyzed the outcomes of patients with relapsed or refractory DLBCL and found that for patients with refractory disease the objective response to salvage therapy was only 26% (7% CR) with a median OS of 6.3 months [1]. CAR-engineered T cells offer a novel and revolutionary therapy for these patients, whom otherwise have very poor outcomes.

Early CAR T-cell trials by Bretjens and colleagues first documented a CR in a subset of patients with refractory hematologic malignancies [2]. Since that time there has been tremendous advancement in CAR T development and clinical application. In the December 2017 issue of the New England Journal of Medicine there were 2 studies published validating the efficacy of CD19-targeted CAR T-cell therapy in relapsed/refractory lymphoma, the current ZUMA-1 study as well as another small case-series by Schuster and colleagues. Schuster et al evaluated the CD19-directed CAR, CTL019, in 28 patients with relapsed/refractory DLBCL or follicular lymphoma. The ORR noted in this study was 64% with a CR rate of 57% [3]. Similarly, in the current ZUMA-1 study the CR rate was 54% in 101 patients with relapsed and refractory large B-cell lymphomas. In addition, with a median follow-up of 15.4 months responses were ongoing in 42% of patients including 40% who had a CR. The durability of such responses has been demonstrated in 3 of 7 patients from the phase 1 portion of this study at 24 months. Durable responses have also been reported with anti-CD19 CAR T-cell therapy in 4 of 5 patients who had a CR and remain in remission after 3-4 years of follow-up [4]. While promising, the durability of responses remains unclear. While CAR therapy represents an exciting therapeutic strategy, it should be noted that in this study approximately 50% of patients will not achieve a durable response and the reason for this is not completely understood.

One of the most discussed aspects of CAR therapy has been the unique toxicity profile, which was again noted in the ZUMA-1 study. As noted, 95% of patients in this study experienced a grade 3 or higher AE. Of interest, cytokine release syndrome occurred in 93% of patients with 13% being grade 3 or higher. There were 2 deaths attributed to such. Neurological toxicity was also noted in 64% of patients in this trial. While the vast majority of these AEs were reversible, they clearly represent high treatment-related morbidity.

The results of the ZUMA-1 study lead to the FDA approval of anti-CD19 CAR T-cell therapy for relapsed or refractory large B-cell lymphoma in October 2017 and represents a pivotal advancement in the management of these patients with otherwise limited treatment options and overall poor outcomes. The ZUMA-1 trial not only demonstrates the efficacy of such agents but also demonstrates the feasibility of incorporating them into clinical practice with a 99% manufacturing success rate and short (median 17 days) product delivery time. The economic burden of such therapies warrant particular consideration as the indications for CAR therapy will continue to expand, driving the cost of care higher. Nevertheless, this represents an exciting step forward in personalized medicine.

Applications for Clinical Practice

CAR T-cell therapy with the CD-19 targeted CAR axicabtagene ciloleucel (axi-cel) results in a high rate of objective and durable responses in patients with relapsed or refractory large B-cell lymphomas. While such treatment does carry a high rate of toxicity in regards to cytokine release and neurological complications, this represents an important treatment option in patients with refractory disease with a historically poor prognosis. However, there will be a need to develop policies to address the economic challenges associated with such treatments.

Loud noise is one of the most common workplace hazards in the US. One-quarter of US workers (an estimated 41 million people) report a history of noise exposure at work—and that may put them at risk for heart disease. According to a Centers for Disease Control and Prevention (CDC) study, high blood pressure and high cholesterol are more common among workers exposed to loud noise at work.

The National Institute for Occupational Safety and Health (NIOSH) researchers analyzed data from the 2014 National Health Interview Survey to estimate the prevalence of occupational noise exposure, hearing difficulty, and heart conditions within US industries and occupations. They also looked at the association between workplace noise exposure and heart disease. Their analysis showed:

• 25% of current workers had a history of work-related noise exposure, 14% were exposed in the last year;
• 12% of current workers had hearing difficulty, 24% had high blood pressure, 28% had high cholesterol; and
• Of those cases 58%, 14%, and 9%, respectively, can be attributed to occupational noise exposure.

Study coauthor Liz Masterson, PhD, says, “If noise could be reduced to safer levels in the workplace, more than 5 million cases of hearing difficulty among noise-exposed workers could potentially be prevented.”

Loud noise is one of the most common workplace hazards in the US. One-quarter of US workers (an estimated 41 million people) report a history of noise exposure at work—and that may put them at risk for heart disease. According to a Centers for Disease Control and Prevention (CDC) study, high blood pressure and high cholesterol are more common among workers exposed to loud noise at work.

The National Institute for Occupational Safety and Health (NIOSH) researchers analyzed data from the 2014 National Health Interview Survey to estimate the prevalence of occupational noise exposure, hearing difficulty, and heart conditions within US industries and occupations. They also looked at the association between workplace noise exposure and heart disease. Their analysis showed:

• 25% of current workers had a history of work-related noise exposure, 14% were exposed in the last year;
• 12% of current workers had hearing difficulty, 24% had high blood pressure, 28% had high cholesterol; and
• Of those cases 58%, 14%, and 9%, respectively, can be attributed to occupational noise exposure.

Study coauthor Liz Masterson, PhD, says, “If noise could be reduced to safer levels in the workplace, more than 5 million cases of hearing difficulty among noise-exposed workers could potentially be prevented.”

Loud noise is one of the most common workplace hazards in the US. One-quarter of US workers (an estimated 41 million people) report a history of noise exposure at work—and that may put them at risk for heart disease. According to a Centers for Disease Control and Prevention (CDC) study, high blood pressure and high cholesterol are more common among workers exposed to loud noise at work.

The National Institute for Occupational Safety and Health (NIOSH) researchers analyzed data from the 2014 National Health Interview Survey to estimate the prevalence of occupational noise exposure, hearing difficulty, and heart conditions within US industries and occupations. They also looked at the association between workplace noise exposure and heart disease. Their analysis showed:

• 25% of current workers had a history of work-related noise exposure, 14% were exposed in the last year;
• 12% of current workers had hearing difficulty, 24% had high blood pressure, 28% had high cholesterol; and
• Of those cases 58%, 14%, and 9%, respectively, can be attributed to occupational noise exposure.

Study coauthor Liz Masterson, PhD, says, “If noise could be reduced to safer levels in the workplace, more than 5 million cases of hearing difficulty among noise-exposed workers could potentially be prevented.”

About 10% to 15% of women in the US have postpartum depression (PPD)—but that estimate is based mostly on women of European ancestry. In black women the rates are doubled, and among Latinas the prevalence is 30% to 43%. But those 2 groups have been inadequately studied, say researchers from University of North Carolina. To help remedy the lack of information, they conducted a study with the largest and “most robustly phenotyped” cohort of minority women with PPD. Their study also is the first to examine genetic ancestry as it contributes to PPD risk.

The researchers recruited 549 women with PPD and 968 without PPD who were within 6 weeks of having given birth. Of those, 67.4% were black, 14.4% were Latina, and 18.2% were white. The median age was 26.7; nearly half of the participants were married. Only 3.6% had given birth for the first time.

The women completed a battery of tests, including the Abuse and Trauma Inventory, Everyday Stressors Index (ESI), Edinburgh Postnatal Depression Scale (EPDS), and Postpartum Bonding Questionnaire. The researchers also assessed estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanolone.

The women with PPD had significantly higher rates of previous psychiatric diagnoses, significantly higher EPDS total scores, and higher rates of family history of PPD. They also had significantly higher rates of previous diagnoses of major depressive disorder (MDD) (53% vs 15%), although 47% were experiencing their first episode of MDD. Dramatically higher numbers of women with PPD vs without PPD had suicidal thoughts in the month prior to assessment: 36% vs 2%, respectively.

Genetic ancestry was not predictive of case status, nor were hormonal influences any different between the 2 groups. Instead, psychiatric history and exposure to adverse life events were significant predictors. Nearly half of all the women with PPD had a lifetime anxiety disorder diagnosis compared with 7% of the controls. And although 67% of all participants reported a history of ≥ 1 traumatic event, women with PPD had double the proportion of multiple events of abuse and trauma. Women who had experienced multiple adverse life events were 3 times more likely to have PPD. Childhood and adult sexual abuse and life-threatening attack were among the most predictive.

The women with PPD had an ESI score > 3 times higher than that of the controls (19% vs 6%, respectively). The researchers note that cumulative lifetime stress may lead to epigenetic modification, and thus to PPD. Women with PPD also had a significantly higher proportion of dysfunctional mother-infant relationships, although the numbers were low in both groups (7% vs 0.35%, respectively).

The researchers say that although genetic ancestry did not play a role in determining case status, there are important ethnic and cultural differences that do play a role in treatment. For instance, Latinas and black women may be less likely to accept antidepressants as therapy. And because socioeconomic status is a determinant of health care access, they also face major barriers to mental health care. However, neither insurance nor education status (markers of socioeconomic status) distinguished cases from controls, even when the researchers controlled for genetic ancestry.

Their data provide a set of risk factors that can be used in screening new mothers, the researchers say. A brief, single assessment for previous psychiatric and abuse/trauma history during the perinatal period, along with regular mood monitoring, could increase a clinician’s ability to predict the onset of PPD.

Source:
Guintivano J, Sullivan PF, Stuebe AM. Psychol Med. 2018;48(7):1190-1200.
doi: 10.1017/S0033291717002641.

About 10% to 15% of women in the US have postpartum depression (PPD)—but that estimate is based mostly on women of European ancestry. In black women the rates are doubled, and among Latinas the prevalence is 30% to 43%. But those 2 groups have been inadequately studied, say researchers from University of North Carolina. To help remedy the lack of information, they conducted a study with the largest and “most robustly phenotyped” cohort of minority women with PPD. Their study also is the first to examine genetic ancestry as it contributes to PPD risk.

The researchers recruited 549 women with PPD and 968 without PPD who were within 6 weeks of having given birth. Of those, 67.4% were black, 14.4% were Latina, and 18.2% were white. The median age was 26.7; nearly half of the participants were married. Only 3.6% had given birth for the first time.

The women completed a battery of tests, including the Abuse and Trauma Inventory, Everyday Stressors Index (ESI), Edinburgh Postnatal Depression Scale (EPDS), and Postpartum Bonding Questionnaire. The researchers also assessed estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanolone.

The women with PPD had significantly higher rates of previous psychiatric diagnoses, significantly higher EPDS total scores, and higher rates of family history of PPD. They also had significantly higher rates of previous diagnoses of major depressive disorder (MDD) (53% vs 15%), although 47% were experiencing their first episode of MDD. Dramatically higher numbers of women with PPD vs without PPD had suicidal thoughts in the month prior to assessment: 36% vs 2%, respectively.

Genetic ancestry was not predictive of case status, nor were hormonal influences any different between the 2 groups. Instead, psychiatric history and exposure to adverse life events were significant predictors. Nearly half of all the women with PPD had a lifetime anxiety disorder diagnosis compared with 7% of the controls. And although 67% of all participants reported a history of ≥ 1 traumatic event, women with PPD had double the proportion of multiple events of abuse and trauma. Women who had experienced multiple adverse life events were 3 times more likely to have PPD. Childhood and adult sexual abuse and life-threatening attack were among the most predictive.

The women with PPD had an ESI score > 3 times higher than that of the controls (19% vs 6%, respectively). The researchers note that cumulative lifetime stress may lead to epigenetic modification, and thus to PPD. Women with PPD also had a significantly higher proportion of dysfunctional mother-infant relationships, although the numbers were low in both groups (7% vs 0.35%, respectively).

The researchers say that although genetic ancestry did not play a role in determining case status, there are important ethnic and cultural differences that do play a role in treatment. For instance, Latinas and black women may be less likely to accept antidepressants as therapy. And because socioeconomic status is a determinant of health care access, they also face major barriers to mental health care. However, neither insurance nor education status (markers of socioeconomic status) distinguished cases from controls, even when the researchers controlled for genetic ancestry.

Their data provide a set of risk factors that can be used in screening new mothers, the researchers say. A brief, single assessment for previous psychiatric and abuse/trauma history during the perinatal period, along with regular mood monitoring, could increase a clinician’s ability to predict the onset of PPD.

Source:
Guintivano J, Sullivan PF, Stuebe AM. Psychol Med. 2018;48(7):1190-1200.
doi: 10.1017/S0033291717002641.

About 10% to 15% of women in the US have postpartum depression (PPD)—but that estimate is based mostly on women of European ancestry. In black women the rates are doubled, and among Latinas the prevalence is 30% to 43%. But those 2 groups have been inadequately studied, say researchers from University of North Carolina. To help remedy the lack of information, they conducted a study with the largest and “most robustly phenotyped” cohort of minority women with PPD. Their study also is the first to examine genetic ancestry as it contributes to PPD risk.

The researchers recruited 549 women with PPD and 968 without PPD who were within 6 weeks of having given birth. Of those, 67.4% were black, 14.4% were Latina, and 18.2% were white. The median age was 26.7; nearly half of the participants were married. Only 3.6% had given birth for the first time.

The women completed a battery of tests, including the Abuse and Trauma Inventory, Everyday Stressors Index (ESI), Edinburgh Postnatal Depression Scale (EPDS), and Postpartum Bonding Questionnaire. The researchers also assessed estradiol, progesterone, brain-derived neurotrophic factor, oxytocin, and allopregnanolone.

The women with PPD had significantly higher rates of previous psychiatric diagnoses, significantly higher EPDS total scores, and higher rates of family history of PPD. They also had significantly higher rates of previous diagnoses of major depressive disorder (MDD) (53% vs 15%), although 47% were experiencing their first episode of MDD. Dramatically higher numbers of women with PPD vs without PPD had suicidal thoughts in the month prior to assessment: 36% vs 2%, respectively.

Genetic ancestry was not predictive of case status, nor were hormonal influences any different between the 2 groups. Instead, psychiatric history and exposure to adverse life events were significant predictors. Nearly half of all the women with PPD had a lifetime anxiety disorder diagnosis compared with 7% of the controls. And although 67% of all participants reported a history of ≥ 1 traumatic event, women with PPD had double the proportion of multiple events of abuse and trauma. Women who had experienced multiple adverse life events were 3 times more likely to have PPD. Childhood and adult sexual abuse and life-threatening attack were among the most predictive.

The women with PPD had an ESI score > 3 times higher than that of the controls (19% vs 6%, respectively). The researchers note that cumulative lifetime stress may lead to epigenetic modification, and thus to PPD. Women with PPD also had a significantly higher proportion of dysfunctional mother-infant relationships, although the numbers were low in both groups (7% vs 0.35%, respectively).

The researchers say that although genetic ancestry did not play a role in determining case status, there are important ethnic and cultural differences that do play a role in treatment. For instance, Latinas and black women may be less likely to accept antidepressants as therapy. And because socioeconomic status is a determinant of health care access, they also face major barriers to mental health care. However, neither insurance nor education status (markers of socioeconomic status) distinguished cases from controls, even when the researchers controlled for genetic ancestry.

Their data provide a set of risk factors that can be used in screening new mothers, the researchers say. A brief, single assessment for previous psychiatric and abuse/trauma history during the perinatal period, along with regular mood monitoring, could increase a clinician’s ability to predict the onset of PPD.

Source:
Guintivano J, Sullivan PF, Stuebe AM. Psychol Med. 2018;48(7):1190-1200.
doi: 10.1017/S0033291717002641.

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Photo by Patrick Pelletier

The availability of generic imatinib has had limited effects on costs of the drug, according to research published in Health Affairs.

Data suggest the cost of Gleevec in the US has more than doubled since the drug was approved in 2001, and the introduction of generic imatinib has reduced costs only slightly.

Two years after generic imatinib hit the market, a month’s supply of Gleevec cost about $9000, and the cost for generic imatinib was about $8000.

“Patients and providers have all looked forward to generic entry, expecting major price reductions,” said study author Stacie Dusetzina, PhD, of Vanderbilt University School of Medicine in Nashville, Tennessee.

“Unfortunately, we don’t see prices drop as quickly and as low as we would hope when generics are available.”

For this study, Dr Dusetzina and a colleague analyzed data from the MarketScan Commercial Research Database. The database contained records of 139,233 prescription fills for imatinib, which were made by 7201 patients from May 2001 through September 2017.

The researchers noted that Gleevec was priced at nearly $4000 for a 1-month (400 mg) supply when it came on the market in 2001. That price escalated to nearly $10,000 by 2015 before a generic competitor entered the market.

However, prices for Gleevec and generic imatinib remained high 2 years later. In 2017, a month’s supply of Gleevec cost about $9000, and the cost of generic imatinib was about $8000.

The researchers said the Gleevec case demonstrates several potential barriers to effective generic price competition, including shifts in prescribing toward more expensive brand-name treatments and smaller-than-expected price reductions.

Twenty-four percent of imatinib (Gleevec) prescriptions claims were for “dispense as written,” according to the researchers. This suggests that patients or providers specifically wanted to stay on the brand-name drug instead of switching to the generic.

“The more than doubling of the drug price over time and the lack of price reductions observed with nearly 2 years of generic drug competition is concerning,” Dr Dusetzina said.

“It begs the question whether we can rely on generic entry as a primary approach to address drug pricing for high-priced specialty medications. We need robust competition to move prices in this space.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Henrique Orlandi Mourao

Researchers have discovered the first leukemia-protective gene that is specific to the Y chromosome, according to an article published in Nature Genetics.

The researchers were investigating how loss of the X-chromosome gene UTX hastens the development of acute myeloid leukemia (AML).

However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The researchers then found that, in AML and other cancers, loss of UTX is accompanied by loss of UTY.

“This is the first Y chromosome-specific gene that protects against AML,” said study author Malgorzata Gozdecka, PhD, of the Wellcome Sanger Institute in Hinxton, UK.

“Previously, it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”

For this work, Dr Gozdecka and her colleagues studied the UTX gene in human cells and mice.

In addition to their discovery that UTY acts as a tumor suppressor gene, the researchers uncovered a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY.

Specifically, the team said UTX suppresses AML by repressing oncogenic ETS and upregulating tumor-suppressive GATA programs. And loss of UTX leads to “altered patterns of gene expression that induce and maintain” AML.

“Treatments for AML have not changed in decades, and there is a large unmet need for new therapies,” said study author George Vassiliou, PhD, of the Wellcome Sanger Institute.

“This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”

Image courtesy of AFIP

Preclinical research helps explain how the JAK1/2 inhibitor ruxolitinib can reduce thrombosis in patients with myeloproliferative neoplasms (MPNs).

Experiments revealed a link between JAK2^V617F and the formation of neutrophil extracellular traps (NETs), which have been implicated in thrombosis.

Researchers found that ruxolitinib reduced NET formation and decreased thrombosis in JAK2-mutant mice.

Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues reported these findings in Science Translational Medicine.

The researchers noted that patients with MPNs have an increased risk of thrombosis, and previous research linked thrombosis to the formation of NETs. NETs are structures that help trap pathogens but may also promote autoimmune responses and excessive blood clotting.

With the current study, Dr Ebert and his colleagues examined whether NET formation could promote thrombosis in patients with MPNs.

The team found that neutrophils from MPN patients were more likely to form NETs than neutrophils from healthy individuals. However, incubating neutrophils with ruxolitinib reduced NET formation.

The researchers also found that mice with JAK2^V617F were more likely to form NETs and develop thrombosis when compared to wild-type mice. However, treatment with ruxolitinib reduced rates of thrombosis and prevented NET formation in the mice.

The researchers noted that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils. And the team found that PAD4 is required for JAK2^V617F-driven NET formation and thrombosis in mouse models of MPNs.

Lastly, the researchers looked at data from 10,893 human subjects. None of these subjects had MPNs, but some had JAK2^V617F.

Subjects who were JAK2^V617F-positive had a significantly higher risk of thrombotic events than subjects without the mutation (P=0.0003).

Taken together, these findings suggest that JAK2 inhibition can reduce NET formation and ameliorate thrombosis in patients with MPNs or the JAK2^V617F mutation.

The researchers noted that, in the phase 3 RESPONSE trial, patients with polycythemia vera had a lower rate of thromboembolic events if they received ruxolitinib rather than standard therapy.

Image courtesy of AFIP

Preclinical research helps explain how the JAK1/2 inhibitor ruxolitinib can reduce thrombosis in patients with myeloproliferative neoplasms (MPNs).

Experiments revealed a link between JAK2^V617F and the formation of neutrophil extracellular traps (NETs), which have been implicated in thrombosis.

Researchers found that ruxolitinib reduced NET formation and decreased thrombosis in JAK2-mutant mice.

Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues reported these findings in Science Translational Medicine.

The researchers noted that patients with MPNs have an increased risk of thrombosis, and previous research linked thrombosis to the formation of NETs. NETs are structures that help trap pathogens but may also promote autoimmune responses and excessive blood clotting.

With the current study, Dr Ebert and his colleagues examined whether NET formation could promote thrombosis in patients with MPNs.

The team found that neutrophils from MPN patients were more likely to form NETs than neutrophils from healthy individuals. However, incubating neutrophils with ruxolitinib reduced NET formation.

The researchers also found that mice with JAK2^V617F were more likely to form NETs and develop thrombosis when compared to wild-type mice. However, treatment with ruxolitinib reduced rates of thrombosis and prevented NET formation in the mice.

The researchers noted that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils. And the team found that PAD4 is required for JAK2^V617F-driven NET formation and thrombosis in mouse models of MPNs.

Lastly, the researchers looked at data from 10,893 human subjects. None of these subjects had MPNs, but some had JAK2^V617F.

Subjects who were JAK2^V617F-positive had a significantly higher risk of thrombotic events than subjects without the mutation (P=0.0003).

Taken together, these findings suggest that JAK2 inhibition can reduce NET formation and ameliorate thrombosis in patients with MPNs or the JAK2^V617F mutation.

The researchers noted that, in the phase 3 RESPONSE trial, patients with polycythemia vera had a lower rate of thromboembolic events if they received ruxolitinib rather than standard therapy.

Image courtesy of AFIP

Preclinical research helps explain how the JAK1/2 inhibitor ruxolitinib can reduce thrombosis in patients with myeloproliferative neoplasms (MPNs).

Experiments revealed a link between JAK2^V617F and the formation of neutrophil extracellular traps (NETs), which have been implicated in thrombosis.

Researchers found that ruxolitinib reduced NET formation and decreased thrombosis in JAK2-mutant mice.

Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues reported these findings in Science Translational Medicine.

The researchers noted that patients with MPNs have an increased risk of thrombosis, and previous research linked thrombosis to the formation of NETs. NETs are structures that help trap pathogens but may also promote autoimmune responses and excessive blood clotting.

With the current study, Dr Ebert and his colleagues examined whether NET formation could promote thrombosis in patients with MPNs.

The team found that neutrophils from MPN patients were more likely to form NETs than neutrophils from healthy individuals. However, incubating neutrophils with ruxolitinib reduced NET formation.

The researchers also found that mice with JAK2^V617F were more likely to form NETs and develop thrombosis when compared to wild-type mice. However, treatment with ruxolitinib reduced rates of thrombosis and prevented NET formation in the mice.

The researchers noted that expression of PAD4, a protein required for NET formation, is increased in JAK2^V617F-expressing neutrophils. And the team found that PAD4 is required for JAK2^V617F-driven NET formation and thrombosis in mouse models of MPNs.

Lastly, the researchers looked at data from 10,893 human subjects. None of these subjects had MPNs, but some had JAK2^V617F.

Subjects who were JAK2^V617F-positive had a significantly higher risk of thrombotic events than subjects without the mutation (P=0.0003).

Taken together, these findings suggest that JAK2 inhibition can reduce NET formation and ameliorate thrombosis in patients with MPNs or the JAK2^V617F mutation.

The researchers noted that, in the phase 3 RESPONSE trial, patients with polycythemia vera had a lower rate of thromboembolic events if they received ruxolitinib rather than standard therapy.

TORONTO – Almost half of adolescents (45%) reported that their primary care providers (PCPs) do not routinely ask them about sex, and only 13% report they’ve been offered screening for sexually transmitted infections (STIs), according to a survey study presented at the Pediatric Academic Societies meeting.

And it appears the teenagers aren’t even listening to much of what their parents are saying on the subject: The survey also found that 90% of parents reported that they talk to their adolescents about sex, but only 39% of adolescents reported the same.

Rawpixel/iStock/Getty Images

“I think that primary care physicians have a lot to cover when doing preventive health visits with adolescents, and talking about sex is not necessarily an easy or comfortable thing to do and so may be something that falls to a lower priority. And it certainly doesn’t help if parents are not supportive of the concept of confidential adolescent care,” Dr. Schneider related.

“We were very surprised to see that 25% of parents did not feel that PCPs should be discussing sex with their child. I think that we need to next work on getting the parents on board and building an expectation that adolescents, when visiting their PCP, will have confidential discussions about sexual health,” she said.

TORONTO – Almost half of adolescents (45%) reported that their primary care providers (PCPs) do not routinely ask them about sex, and only 13% report they’ve been offered screening for sexually transmitted infections (STIs), according to a survey study presented at the Pediatric Academic Societies meeting.

And it appears the teenagers aren’t even listening to much of what their parents are saying on the subject: The survey also found that 90% of parents reported that they talk to their adolescents about sex, but only 39% of adolescents reported the same.

Rawpixel/iStock/Getty Images

“I think that primary care physicians have a lot to cover when doing preventive health visits with adolescents, and talking about sex is not necessarily an easy or comfortable thing to do and so may be something that falls to a lower priority. And it certainly doesn’t help if parents are not supportive of the concept of confidential adolescent care,” Dr. Schneider related.

“We were very surprised to see that 25% of parents did not feel that PCPs should be discussing sex with their child. I think that we need to next work on getting the parents on board and building an expectation that adolescents, when visiting their PCP, will have confidential discussions about sexual health,” she said.

TORONTO – Almost half of adolescents (45%) reported that their primary care providers (PCPs) do not routinely ask them about sex, and only 13% report they’ve been offered screening for sexually transmitted infections (STIs), according to a survey study presented at the Pediatric Academic Societies meeting.

And it appears the teenagers aren’t even listening to much of what their parents are saying on the subject: The survey also found that 90% of parents reported that they talk to their adolescents about sex, but only 39% of adolescents reported the same.

Rawpixel/iStock/Getty Images

“I think that primary care physicians have a lot to cover when doing preventive health visits with adolescents, and talking about sex is not necessarily an easy or comfortable thing to do and so may be something that falls to a lower priority. And it certainly doesn’t help if parents are not supportive of the concept of confidential adolescent care,” Dr. Schneider related.

“We were very surprised to see that 25% of parents did not feel that PCPs should be discussing sex with their child. I think that we need to next work on getting the parents on board and building an expectation that adolescents, when visiting their PCP, will have confidential discussions about sexual health,” she said.

NEW YORK – Veterans are not a homogeneous group, and when treating them for posttraumatic stress, it helps to consider their specific cohort, according to Elspeth Cameron Ritchie, MD.

Veterans from the first Gulf War, for example, have lingering concerns regarding medical illness (Gulf War syndrome); those from Vietnam are aging and might have medical problems or find that while they did well while working, now they are experiencing PTSD symptoms for the first time; and those returning from the conflicts in Iraq and Afghanistan might have physical injuries from blasts – the “signature weapon” of those wars. Such blasts can cause amputations, genital injuries, head trauma, and PTSD, said Dr. Ritchie, of the Uniformed Services University of the Health Sciences, Bethesda, Md.

In this video interview, Dr. Ritchie discusses these and other issues related to the treatment of PTSD among veterans as presented during a workshop entitled “Psychiatry and U.S. Veterans,” which she chaired at the annual meeting of the American Psychiatric Association.

The workshop covered the spectrum of treatments that might be helpful for veterans.

“One thing I find with veterans is that they really want to have control over their treatment. They don’t want it to just be the doctor giving them a pill,” she said. “Veterans are resilient; they’re tough; they don’t like to be thought of as victims ... and when you’re working with them, it’s very important to link into that dynamic resilient piece and capitalize on their strengths.”

Dr. Ritchie reported having no disclosures.

sworcester@mdedge.com

SOURCE: Ritchie EC et al. APA Workshop.

NEW YORK – Veterans are not a homogeneous group, and when treating them for posttraumatic stress, it helps to consider their specific cohort, according to Elspeth Cameron Ritchie, MD.

Veterans from the first Gulf War, for example, have lingering concerns regarding medical illness (Gulf War syndrome); those from Vietnam are aging and might have medical problems or find that while they did well while working, now they are experiencing PTSD symptoms for the first time; and those returning from the conflicts in Iraq and Afghanistan might have physical injuries from blasts – the “signature weapon” of those wars. Such blasts can cause amputations, genital injuries, head trauma, and PTSD, said Dr. Ritchie, of the Uniformed Services University of the Health Sciences, Bethesda, Md.

In this video interview, Dr. Ritchie discusses these and other issues related to the treatment of PTSD among veterans as presented during a workshop entitled “Psychiatry and U.S. Veterans,” which she chaired at the annual meeting of the American Psychiatric Association.

The workshop covered the spectrum of treatments that might be helpful for veterans.

“One thing I find with veterans is that they really want to have control over their treatment. They don’t want it to just be the doctor giving them a pill,” she said. “Veterans are resilient; they’re tough; they don’t like to be thought of as victims ... and when you’re working with them, it’s very important to link into that dynamic resilient piece and capitalize on their strengths.”

Dr. Ritchie reported having no disclosures.

sworcester@mdedge.com

SOURCE: Ritchie EC et al. APA Workshop.

NEW YORK – Veterans are not a homogeneous group, and when treating them for posttraumatic stress, it helps to consider their specific cohort, according to Elspeth Cameron Ritchie, MD.

Veterans from the first Gulf War, for example, have lingering concerns regarding medical illness (Gulf War syndrome); those from Vietnam are aging and might have medical problems or find that while they did well while working, now they are experiencing PTSD symptoms for the first time; and those returning from the conflicts in Iraq and Afghanistan might have physical injuries from blasts – the “signature weapon” of those wars. Such blasts can cause amputations, genital injuries, head trauma, and PTSD, said Dr. Ritchie, of the Uniformed Services University of the Health Sciences, Bethesda, Md.

In this video interview, Dr. Ritchie discusses these and other issues related to the treatment of PTSD among veterans as presented during a workshop entitled “Psychiatry and U.S. Veterans,” which she chaired at the annual meeting of the American Psychiatric Association.

The workshop covered the spectrum of treatments that might be helpful for veterans.

“One thing I find with veterans is that they really want to have control over their treatment. They don’t want it to just be the doctor giving them a pill,” she said. “Veterans are resilient; they’re tough; they don’t like to be thought of as victims ... and when you’re working with them, it’s very important to link into that dynamic resilient piece and capitalize on their strengths.”

Dr. Ritchie reported having no disclosures.

sworcester@mdedge.com

SOURCE: Ritchie EC et al. APA Workshop.

Ivacaftor, a therapy that targets the G551D CFTR gene mutation to treat cystic fibrosis, significantly reduced hospital admission rates in patients with cystic fibrosis with a variety of mutations, according to results published May 7 in Health Affairs.

The study involved 143 patients being treated with ivacaftor between February 2012 and February 2015. In 2014, the FDA expanded its approval for the use of ivacaftor by cystic fibrosis patients to include nine additional mutations, and patients with these mutations were included in this study.

copyright Zerbor/Thinkstock

SOURCE: Feng LB et al. Health Aff. 2018 May 8. doi: 10.1377/hlthaff.2017.1554

Ivacaftor, a therapy that targets the G551D CFTR gene mutation to treat cystic fibrosis, significantly reduced hospital admission rates in patients with cystic fibrosis with a variety of mutations, according to results published May 7 in Health Affairs.

The study involved 143 patients being treated with ivacaftor between February 2012 and February 2015. In 2014, the FDA expanded its approval for the use of ivacaftor by cystic fibrosis patients to include nine additional mutations, and patients with these mutations were included in this study.

copyright Zerbor/Thinkstock

SOURCE: Feng LB et al. Health Aff. 2018 May 8. doi: 10.1377/hlthaff.2017.1554

Ivacaftor, a therapy that targets the G551D CFTR gene mutation to treat cystic fibrosis, significantly reduced hospital admission rates in patients with cystic fibrosis with a variety of mutations, according to results published May 7 in Health Affairs.

The study involved 143 patients being treated with ivacaftor between February 2012 and February 2015. In 2014, the FDA expanded its approval for the use of ivacaftor by cystic fibrosis patients to include nine additional mutations, and patients with these mutations were included in this study.

copyright Zerbor/Thinkstock

SOURCE: Feng LB et al. Health Aff. 2018 May 8. doi: 10.1377/hlthaff.2017.1554

The HOPE in Action Multicenter Kidney Study, the first large-scale clinical trial to study kidney transplantations between people with HIV, has begun at clinical centers across the United States, according to an announcement by the National Institutes of Health. The study, sponsored by the National Institute of Allergy and Infectious Diseases and NIH, will assess the safety of HIV-positive donor to HIV-positive recipient kidney transplantation. This form of transplantation was made legal by the passage of the HOPE (HIV Organ Policy Equity) Act, which permits the transplantation of organs from donors with HIV into qualified HIV-positive recipients with end-stage organ failure.

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Outcomes to be studied in the multicenter trial will include potential transplant-related and HIV-related complications following surgery, as well as organ rejection, organ failure, and failure of previously effective HIV medications. The study is currently enrolling and is expected to include 360 participants, with an estimated completion date of Aug. 1, 2022.

“The HOPE Act of 2013 opened the door for researchers to explore a potential new source of donor organs for those living with HIV – a population with a significant and growing need for transplants. This study offers a chance to improve the health of those living with HIV, and increase the overall supply of transplantable organs,” said NIAID Director Anthony S. Fauci, MD, in the NIH news release. Transplantation of organs from HIV-positive donors to HIV-negative recipients remains illegal in the United States.

More information about the study can be found at ClinicalTrials.gov using the identifier NCT03500315. A similar trial to examine liver transplantation, the HOPE in Action Multicenter Liver Study, is expected to launch later in 2018.

mlesney@mdedge.com

The HOPE in Action Multicenter Kidney Study, the first large-scale clinical trial to study kidney transplantations between people with HIV, has begun at clinical centers across the United States, according to an announcement by the National Institutes of Health. The study, sponsored by the National Institute of Allergy and Infectious Diseases and NIH, will assess the safety of HIV-positive donor to HIV-positive recipient kidney transplantation. This form of transplantation was made legal by the passage of the HOPE (HIV Organ Policy Equity) Act, which permits the transplantation of organs from donors with HIV into qualified HIV-positive recipients with end-stage organ failure.

London_England/Thinkstock

Outcomes to be studied in the multicenter trial will include potential transplant-related and HIV-related complications following surgery, as well as organ rejection, organ failure, and failure of previously effective HIV medications. The study is currently enrolling and is expected to include 360 participants, with an estimated completion date of Aug. 1, 2022.

“The HOPE Act of 2013 opened the door for researchers to explore a potential new source of donor organs for those living with HIV – a population with a significant and growing need for transplants. This study offers a chance to improve the health of those living with HIV, and increase the overall supply of transplantable organs,” said NIAID Director Anthony S. Fauci, MD, in the NIH news release. Transplantation of organs from HIV-positive donors to HIV-negative recipients remains illegal in the United States.

More information about the study can be found at ClinicalTrials.gov using the identifier NCT03500315. A similar trial to examine liver transplantation, the HOPE in Action Multicenter Liver Study, is expected to launch later in 2018.

mlesney@mdedge.com

The HOPE in Action Multicenter Kidney Study, the first large-scale clinical trial to study kidney transplantations between people with HIV, has begun at clinical centers across the United States, according to an announcement by the National Institutes of Health. The study, sponsored by the National Institute of Allergy and Infectious Diseases and NIH, will assess the safety of HIV-positive donor to HIV-positive recipient kidney transplantation. This form of transplantation was made legal by the passage of the HOPE (HIV Organ Policy Equity) Act, which permits the transplantation of organs from donors with HIV into qualified HIV-positive recipients with end-stage organ failure.

London_England/Thinkstock

Outcomes to be studied in the multicenter trial will include potential transplant-related and HIV-related complications following surgery, as well as organ rejection, organ failure, and failure of previously effective HIV medications. The study is currently enrolling and is expected to include 360 participants, with an estimated completion date of Aug. 1, 2022.

“The HOPE Act of 2013 opened the door for researchers to explore a potential new source of donor organs for those living with HIV – a population with a significant and growing need for transplants. This study offers a chance to improve the health of those living with HIV, and increase the overall supply of transplantable organs,” said NIAID Director Anthony S. Fauci, MD, in the NIH news release. Transplantation of organs from HIV-positive donors to HIV-negative recipients remains illegal in the United States.

More information about the study can be found at ClinicalTrials.gov using the identifier NCT03500315. A similar trial to examine liver transplantation, the HOPE in Action Multicenter Liver Study, is expected to launch later in 2018.

mlesney@mdedge.com