Stem cells for transplant
Photo by Chad McNeeley

CHICAGO—A phase 3 study of tandem autologous stem cell transplant (ASCT) for children with high-risk neuroblastoma has shown that tandem transplant as consolidation significantly improved event-free survival (EFS). 

Nevertheless, the improvement comes “with an important caveat,” according to Julie R. Park, MD, “that this is in children who survive induction without disease progression after induction or severe induction-related toxicity.” 

Of note, the tandem transplant did not increase toxicity or regimen-related mortality.

Dr Park, of the Seattle Children’s Hospital and University of Washington, presented the study data on behalf of the Children’s Oncology Group and the COG ANBL0532 Study Committee during the plenary session at the 2016 ASCO Annual Meeting (LBA3*).

Neuroblastoma, Dr Park explained, is a disease that occurs in young children and is the most common extracranial tumor of childhood. Patients with high-risk neuroblastoma account for 50% of all children diagnosed with the disease, and neuroblastoma accounts for more than 10% of all childhood cancer mortality. 

The outcome for high-risk neuroblastoma patients is dismal: fewer than 50% survive following current multi-agent, aggressive therapy, she said. 

Randomized clinical trials performed over the last 25 years “have taught us that dose intensification of therapy is important,” Dr Park said, “and the treatment of minimal residual disease with non-cross resistant therapies is equally important.” 

Pilot studies of tandem ASCT demonstrated tolerable toxicity and suggested efficacy, and clinical trials demonstrated that collecting peripheral blood stem cells in small children with neuroblastoma was feasible. 

So the investigators undertook the current study to improve 3-year EFS of high-risk neuroblastoma patients using a strategy of tandem transplant consolidation.

Eligibility

Patients with newly diagnosed high-risk neuroblastoma were eligible. They had to have metastatic disease (INSS stage 4) and be older than 18 months to be eligible for the trial.

They could be any age if they had INSS stage 2, 3, or 4 with MYCN amplification.

“Our prior studies had identified that the group with regional disease and toddlers with MYCN non-amplified metastatic disease had a better outcome compared to other children with high-risk neuroblastoma,” Dr Park commented. 

“Therefore, these children were non-randomly assigned to single transplant and are not included in the randomization results provided today,” she explained.

All children had to have normal cardiac, liver, and renal function.

Trial design: Induction

Induction therapy consisted of 6 cycles of chemotherapy—2 cycles of cyclophosphamide/topotecan, followed by 4 alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin. 

Peripheral blood stem cells (PBSCs) were harvested after the first 2 cycles of dose intensive cyclophosphamide and topotecan.  

Patients had surgery on the primary tumor after 5 cycles of induction.

Trial design: Consolidation

Following completion of induction therapy, patients were assessed for eligibility for consolidation. These criteria included sufficient PBSC harvest, adequate organ function, no evidence of disease progression, and consent for post induction therapy.

Children eligible for consolidation were randomized to either the standard transplant with carboplatin, etoposide, melphalan or tandem transplant with cyclophosphamide and thiotepa followed 6 – 8 weeks later by the second transplant with carboplatin, etoposide, and melphalan.

Patients in both arms received radiotherapy to their primary tumor site. 

Trial Design: Post-consolidation

Patients then went on for post consolidation chemotherapy with isotretinoin.

“During the conduct of ANBL0532,” Dr Park pointed out, “there was an additional trial running within the Children’s Oncology Group for which patients were eligible to enroll.”

So from 2007 – 2009, the additional trial (ANBL0032) randomized patients to their then standard of isotretinoin or isotretinoin plus the anti-GD2 antibody dinutuximab and cytokines.

“In 2009, results of that study were released and the dinutuximab arm was superior,” she noted, so patients were no longer randomized to isotretinoin only.

Prior studies indicated that 40% of patients went off trial at the end of induction therapy, so the investigators enrolled 665 patients to ensure a randomization of at least 332 patients. 

Data cut-off for the presentation was March 31, 2016.

Patient demographics

Of the 665 patients accrued, 13 were ineligible. Twenty-seven patients with favorable prognosis were non-randomly assigned to single ASCT.

Forty percent (229 patients) went off protocol therapy prior to randomization. The main reasons for this were death (8 patients), progressive disease (48 patients), and physician and patient discretion (206 patients).

Investigators randomized 355 patients, 179 to single ASCT and 176 to tandem ASCT.

Patients were a median age of 37.2 months, 38.2% had MYCN amplification, and 88% were INSS stage 4.

The randomized cohorts of patients were similar to the overall patient cohort in terms of age, MYCN amplification, and stage 4 disease.

The randomizations were also well balanced in terms of MYCN amplifications, stage 4 disease, and response to induction chemotherapy.

The investigators retrospectively reviewed the patient characteristics, including age at diagnosis, early response to induction, and assignment to receive immunotherapy, “and there was no statistically significant difference between the randomized cohorts for these characteristics,” Dr Park said.

Safety

The most commonly observed grade 3 or greater non-hematologic toxicities in the single and tandem arms included infection (18.3% and 17.9%, respectively), mucosal toxicities (17.2% and 13.6%, respectively), and hepatic toxicities, including sinusoidal obstructive disorder (6.5% and 6.2%, respectively). 

The investigators observed no significant differences between the arms in regard to the rate of these toxicities. In addition, they observed no difference between the arms in the rate of regimen-related mortality, 4.1% in the single arm, and 1.2% in the tandem arm.

Efficacy

For all patients (n=652) from time of enrollment, the 3-year EFS was 51.0% and the 3-year OS was 68.3%.

In randomized patients (n=355), from the time of randomization, the 3-year EFS was 54.8% and the 3-year OS, 71.5%, with a median survival time of 4.6 years.

There was a statistically significant improvement in EFS for those patients assigned to tandem transplant, with a 3-year EFS of 61.4% as compared to those assigned to single transplant, who had a 3-year EFS of 48.4% (P=0.0081).

There was not a statistically significant difference in OS. However, Dr Park pointed out that the trial was not powered to detect a difference in overall survival. 

When looking at the cohort of stage 4 patients who were older than 18 months, investigators again saw a statistically significant improvement in EFS. The 3-year EFS was 59%.1 for tandem transplants vs 45.5% for single transplants, P=0.0083.

Again, there was no difference in OS in the INSS stage 4 patients older than 18 months.

“And finally, when we analyzed the outcome for children who were assigned to receive immunotherapy,” Dr Park pointed out, “from the time of start of immunotherapy, there was a statistically significant improvement in both event-free survival and overall survival for those children who received tandem transplants.”

The 3-year EFS for patients who received a tandem transplant and immunotherapy was 73.7% compared to the 3-year EFS of 56.0% for patients who received a single transplant and immunotherapy (P=0.0033). 

The 3-year overall survival was also significantly improved for patients who received tandem transplants and immunotherapy (83.7%) compared to those who received a single transplant and immunotherapy (74.4%) (P=0.0322).

Conclusions

“Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma,” Dr Park said, with the important caveat mentioned earlier.

The tandem transplant does not increase toxicity or regimen-related mortality, and the benefit of tandem ASCT remains following anti-GD2-directed immunotherapy.

*Data in the presentation differ slightly from the abstract

Stem cells for transplant
Photo by Chad McNeeley

CHICAGO—A phase 3 study of tandem autologous stem cell transplant (ASCT) for children with high-risk neuroblastoma has shown that tandem transplant as consolidation significantly improved event-free survival (EFS). 

Nevertheless, the improvement comes “with an important caveat,” according to Julie R. Park, MD, “that this is in children who survive induction without disease progression after induction or severe induction-related toxicity.” 

Of note, the tandem transplant did not increase toxicity or regimen-related mortality.

Dr Park, of the Seattle Children’s Hospital and University of Washington, presented the study data on behalf of the Children’s Oncology Group and the COG ANBL0532 Study Committee during the plenary session at the 2016 ASCO Annual Meeting (LBA3*).

Neuroblastoma, Dr Park explained, is a disease that occurs in young children and is the most common extracranial tumor of childhood. Patients with high-risk neuroblastoma account for 50% of all children diagnosed with the disease, and neuroblastoma accounts for more than 10% of all childhood cancer mortality. 

The outcome for high-risk neuroblastoma patients is dismal: fewer than 50% survive following current multi-agent, aggressive therapy, she said. 

Randomized clinical trials performed over the last 25 years “have taught us that dose intensification of therapy is important,” Dr Park said, “and the treatment of minimal residual disease with non-cross resistant therapies is equally important.” 

Pilot studies of tandem ASCT demonstrated tolerable toxicity and suggested efficacy, and clinical trials demonstrated that collecting peripheral blood stem cells in small children with neuroblastoma was feasible. 

So the investigators undertook the current study to improve 3-year EFS of high-risk neuroblastoma patients using a strategy of tandem transplant consolidation.

Eligibility

Patients with newly diagnosed high-risk neuroblastoma were eligible. They had to have metastatic disease (INSS stage 4) and be older than 18 months to be eligible for the trial.

They could be any age if they had INSS stage 2, 3, or 4 with MYCN amplification.

“Our prior studies had identified that the group with regional disease and toddlers with MYCN non-amplified metastatic disease had a better outcome compared to other children with high-risk neuroblastoma,” Dr Park commented. 

“Therefore, these children were non-randomly assigned to single transplant and are not included in the randomization results provided today,” she explained.

All children had to have normal cardiac, liver, and renal function.

Trial design: Induction

Induction therapy consisted of 6 cycles of chemotherapy—2 cycles of cyclophosphamide/topotecan, followed by 4 alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin. 

Peripheral blood stem cells (PBSCs) were harvested after the first 2 cycles of dose intensive cyclophosphamide and topotecan.  

Patients had surgery on the primary tumor after 5 cycles of induction.

Trial design: Consolidation

Following completion of induction therapy, patients were assessed for eligibility for consolidation. These criteria included sufficient PBSC harvest, adequate organ function, no evidence of disease progression, and consent for post induction therapy.

Children eligible for consolidation were randomized to either the standard transplant with carboplatin, etoposide, melphalan or tandem transplant with cyclophosphamide and thiotepa followed 6 – 8 weeks later by the second transplant with carboplatin, etoposide, and melphalan.

Patients in both arms received radiotherapy to their primary tumor site. 

Trial Design: Post-consolidation

Patients then went on for post consolidation chemotherapy with isotretinoin.

“During the conduct of ANBL0532,” Dr Park pointed out, “there was an additional trial running within the Children’s Oncology Group for which patients were eligible to enroll.”

So from 2007 – 2009, the additional trial (ANBL0032) randomized patients to their then standard of isotretinoin or isotretinoin plus the anti-GD2 antibody dinutuximab and cytokines.

“In 2009, results of that study were released and the dinutuximab arm was superior,” she noted, so patients were no longer randomized to isotretinoin only.

Prior studies indicated that 40% of patients went off trial at the end of induction therapy, so the investigators enrolled 665 patients to ensure a randomization of at least 332 patients. 

Data cut-off for the presentation was March 31, 2016.

Patient demographics

Of the 665 patients accrued, 13 were ineligible. Twenty-seven patients with favorable prognosis were non-randomly assigned to single ASCT.

Forty percent (229 patients) went off protocol therapy prior to randomization. The main reasons for this were death (8 patients), progressive disease (48 patients), and physician and patient discretion (206 patients).

Investigators randomized 355 patients, 179 to single ASCT and 176 to tandem ASCT.

Patients were a median age of 37.2 months, 38.2% had MYCN amplification, and 88% were INSS stage 4.

The randomized cohorts of patients were similar to the overall patient cohort in terms of age, MYCN amplification, and stage 4 disease.

The randomizations were also well balanced in terms of MYCN amplifications, stage 4 disease, and response to induction chemotherapy.

The investigators retrospectively reviewed the patient characteristics, including age at diagnosis, early response to induction, and assignment to receive immunotherapy, “and there was no statistically significant difference between the randomized cohorts for these characteristics,” Dr Park said.

Safety

The most commonly observed grade 3 or greater non-hematologic toxicities in the single and tandem arms included infection (18.3% and 17.9%, respectively), mucosal toxicities (17.2% and 13.6%, respectively), and hepatic toxicities, including sinusoidal obstructive disorder (6.5% and 6.2%, respectively). 

The investigators observed no significant differences between the arms in regard to the rate of these toxicities. In addition, they observed no difference between the arms in the rate of regimen-related mortality, 4.1% in the single arm, and 1.2% in the tandem arm.

Efficacy

For all patients (n=652) from time of enrollment, the 3-year EFS was 51.0% and the 3-year OS was 68.3%.

In randomized patients (n=355), from the time of randomization, the 3-year EFS was 54.8% and the 3-year OS, 71.5%, with a median survival time of 4.6 years.

There was a statistically significant improvement in EFS for those patients assigned to tandem transplant, with a 3-year EFS of 61.4% as compared to those assigned to single transplant, who had a 3-year EFS of 48.4% (P=0.0081).

There was not a statistically significant difference in OS. However, Dr Park pointed out that the trial was not powered to detect a difference in overall survival. 

When looking at the cohort of stage 4 patients who were older than 18 months, investigators again saw a statistically significant improvement in EFS. The 3-year EFS was 59%.1 for tandem transplants vs 45.5% for single transplants, P=0.0083.

Again, there was no difference in OS in the INSS stage 4 patients older than 18 months.

“And finally, when we analyzed the outcome for children who were assigned to receive immunotherapy,” Dr Park pointed out, “from the time of start of immunotherapy, there was a statistically significant improvement in both event-free survival and overall survival for those children who received tandem transplants.”

The 3-year EFS for patients who received a tandem transplant and immunotherapy was 73.7% compared to the 3-year EFS of 56.0% for patients who received a single transplant and immunotherapy (P=0.0033). 

The 3-year overall survival was also significantly improved for patients who received tandem transplants and immunotherapy (83.7%) compared to those who received a single transplant and immunotherapy (74.4%) (P=0.0322).

Conclusions

“Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma,” Dr Park said, with the important caveat mentioned earlier.

The tandem transplant does not increase toxicity or regimen-related mortality, and the benefit of tandem ASCT remains following anti-GD2-directed immunotherapy.

*Data in the presentation differ slightly from the abstract

Stem cells for transplant
Photo by Chad McNeeley

CHICAGO—A phase 3 study of tandem autologous stem cell transplant (ASCT) for children with high-risk neuroblastoma has shown that tandem transplant as consolidation significantly improved event-free survival (EFS). 

Nevertheless, the improvement comes “with an important caveat,” according to Julie R. Park, MD, “that this is in children who survive induction without disease progression after induction or severe induction-related toxicity.” 

Of note, the tandem transplant did not increase toxicity or regimen-related mortality.

Dr Park, of the Seattle Children’s Hospital and University of Washington, presented the study data on behalf of the Children’s Oncology Group and the COG ANBL0532 Study Committee during the plenary session at the 2016 ASCO Annual Meeting (LBA3*).

Neuroblastoma, Dr Park explained, is a disease that occurs in young children and is the most common extracranial tumor of childhood. Patients with high-risk neuroblastoma account for 50% of all children diagnosed with the disease, and neuroblastoma accounts for more than 10% of all childhood cancer mortality. 

The outcome for high-risk neuroblastoma patients is dismal: fewer than 50% survive following current multi-agent, aggressive therapy, she said. 

Randomized clinical trials performed over the last 25 years “have taught us that dose intensification of therapy is important,” Dr Park said, “and the treatment of minimal residual disease with non-cross resistant therapies is equally important.” 

Pilot studies of tandem ASCT demonstrated tolerable toxicity and suggested efficacy, and clinical trials demonstrated that collecting peripheral blood stem cells in small children with neuroblastoma was feasible. 

So the investigators undertook the current study to improve 3-year EFS of high-risk neuroblastoma patients using a strategy of tandem transplant consolidation.

Eligibility

Patients with newly diagnosed high-risk neuroblastoma were eligible. They had to have metastatic disease (INSS stage 4) and be older than 18 months to be eligible for the trial.

They could be any age if they had INSS stage 2, 3, or 4 with MYCN amplification.

“Our prior studies had identified that the group with regional disease and toddlers with MYCN non-amplified metastatic disease had a better outcome compared to other children with high-risk neuroblastoma,” Dr Park commented. 

“Therefore, these children were non-randomly assigned to single transplant and are not included in the randomization results provided today,” she explained.

All children had to have normal cardiac, liver, and renal function.

Trial design: Induction

Induction therapy consisted of 6 cycles of chemotherapy—2 cycles of cyclophosphamide/topotecan, followed by 4 alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin. 

Peripheral blood stem cells (PBSCs) were harvested after the first 2 cycles of dose intensive cyclophosphamide and topotecan.  

Patients had surgery on the primary tumor after 5 cycles of induction.

Trial design: Consolidation

Following completion of induction therapy, patients were assessed for eligibility for consolidation. These criteria included sufficient PBSC harvest, adequate organ function, no evidence of disease progression, and consent for post induction therapy.

Children eligible for consolidation were randomized to either the standard transplant with carboplatin, etoposide, melphalan or tandem transplant with cyclophosphamide and thiotepa followed 6 – 8 weeks later by the second transplant with carboplatin, etoposide, and melphalan.

Patients in both arms received radiotherapy to their primary tumor site. 

Trial Design: Post-consolidation

Patients then went on for post consolidation chemotherapy with isotretinoin.

“During the conduct of ANBL0532,” Dr Park pointed out, “there was an additional trial running within the Children’s Oncology Group for which patients were eligible to enroll.”

So from 2007 – 2009, the additional trial (ANBL0032) randomized patients to their then standard of isotretinoin or isotretinoin plus the anti-GD2 antibody dinutuximab and cytokines.

“In 2009, results of that study were released and the dinutuximab arm was superior,” she noted, so patients were no longer randomized to isotretinoin only.

Prior studies indicated that 40% of patients went off trial at the end of induction therapy, so the investigators enrolled 665 patients to ensure a randomization of at least 332 patients. 

Data cut-off for the presentation was March 31, 2016.

Patient demographics

Of the 665 patients accrued, 13 were ineligible. Twenty-seven patients with favorable prognosis were non-randomly assigned to single ASCT.

Forty percent (229 patients) went off protocol therapy prior to randomization. The main reasons for this were death (8 patients), progressive disease (48 patients), and physician and patient discretion (206 patients).

Investigators randomized 355 patients, 179 to single ASCT and 176 to tandem ASCT.

Patients were a median age of 37.2 months, 38.2% had MYCN amplification, and 88% were INSS stage 4.

The randomized cohorts of patients were similar to the overall patient cohort in terms of age, MYCN amplification, and stage 4 disease.

The randomizations were also well balanced in terms of MYCN amplifications, stage 4 disease, and response to induction chemotherapy.

The investigators retrospectively reviewed the patient characteristics, including age at diagnosis, early response to induction, and assignment to receive immunotherapy, “and there was no statistically significant difference between the randomized cohorts for these characteristics,” Dr Park said.

Safety

The most commonly observed grade 3 or greater non-hematologic toxicities in the single and tandem arms included infection (18.3% and 17.9%, respectively), mucosal toxicities (17.2% and 13.6%, respectively), and hepatic toxicities, including sinusoidal obstructive disorder (6.5% and 6.2%, respectively). 

The investigators observed no significant differences between the arms in regard to the rate of these toxicities. In addition, they observed no difference between the arms in the rate of regimen-related mortality, 4.1% in the single arm, and 1.2% in the tandem arm.

Efficacy

For all patients (n=652) from time of enrollment, the 3-year EFS was 51.0% and the 3-year OS was 68.3%.

In randomized patients (n=355), from the time of randomization, the 3-year EFS was 54.8% and the 3-year OS, 71.5%, with a median survival time of 4.6 years.

There was a statistically significant improvement in EFS for those patients assigned to tandem transplant, with a 3-year EFS of 61.4% as compared to those assigned to single transplant, who had a 3-year EFS of 48.4% (P=0.0081).

There was not a statistically significant difference in OS. However, Dr Park pointed out that the trial was not powered to detect a difference in overall survival. 

When looking at the cohort of stage 4 patients who were older than 18 months, investigators again saw a statistically significant improvement in EFS. The 3-year EFS was 59%.1 for tandem transplants vs 45.5% for single transplants, P=0.0083.

Again, there was no difference in OS in the INSS stage 4 patients older than 18 months.

“And finally, when we analyzed the outcome for children who were assigned to receive immunotherapy,” Dr Park pointed out, “from the time of start of immunotherapy, there was a statistically significant improvement in both event-free survival and overall survival for those children who received tandem transplants.”

The 3-year EFS for patients who received a tandem transplant and immunotherapy was 73.7% compared to the 3-year EFS of 56.0% for patients who received a single transplant and immunotherapy (P=0.0033). 

The 3-year overall survival was also significantly improved for patients who received tandem transplants and immunotherapy (83.7%) compared to those who received a single transplant and immunotherapy (74.4%) (P=0.0322).

Conclusions

“Tandem transplant consolidation improves outcome in patients with high-risk neuroblastoma,” Dr Park said, with the important caveat mentioned earlier.

The tandem transplant does not increase toxicity or regimen-related mortality, and the benefit of tandem ASCT remains following anti-GD2-directed immunotherapy.

*Data in the presentation differ slightly from the abstract

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

MRI scan of the brain

New research has found that higher blood concentrations of methotrexate in pediatric leukemia patients during treatment results in difficulties with mental flexibility, organization, and related skills for the long-term survivors. 

And in patients with acute lymphoblastic leukemia (ALL) who had higher levels of methotrexate during treatment, brain imaging showed anatomical and functional changes in regions of the brain involved with executive functioning. Methotrexate is one of the few chemotherapy agents that crosses the blood–brain barrier. 

“This study is the first to show a clear dose-response effect between methotrexate concentrations in the blood during treatment and executive functioning in survivors,” lead author Kevin Krull, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, said. 

“This information is essential for designing effective interventions to address the risk,” he said.

To examine the association between methotrexate exposure and neurocognitive outcomes, the investigators enrolled 218 long-term pediatric ALL survivors who participated in the St Jude Total Therapy XV clinical trial between 2000 and 2010. 

The patients had been treated with multidrug chemotherapy according to the Total Therapy XV protocol, which included intrathecal treatments with methotrexate, hydrocortisone, and cytarabine in addition to other chemotherapeutic agents.

Researchers calculated methotrexate concentrations by measuring blood levels of the drug before, during, and after treatment. They also checked blood levels of the amino acid homocysteine, a marker of methotrexate activity, and the chemotherapy agent dexamethasone.

All patients had survived at least 5 years from their diagnosis and were at least 8 years old when this study was conducted.

Investigators performed neurocognitive testing, functional magnetic resonance imaging (MRI) during a task, and structural MRI with diffusion tensor imaging.

At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis. Fifty-one percent were male, 74% were white, and 57% were in the low-risk treatment stratum.

Investigators found that the survivors’ intelligence was within normal limits compared with population expectations.

However, they found measures of executive function, processing speed, and memory to be less than population means, with a significance of P<0.02 after correction for false discovery rates.

And while impact of methotrexate varied, some survivors had executive functioning scores that indicated moderate to almost severe impairment. 

Investigators also found higher plasma methotrexate to be associated with higher functional MRI activity, thicker cortex, and higher activity in frontal brain regions, regions often associated with executive function.

The investigators found neurocognitive impairment also to be associated with these imaging findings .

The increased activity in the frontal lobe region suggests that survivors’ brains may be working harder to compensate for impaired cognitive function, the investigators believe.

When they adjusted for age or dose of leucovorin rescue, these associations did not change.

And consistent with the methotrexate exposure, elevated homocysteine levels during therapy were associated with poorer cognitive flexibility.

The authors noted that they did not find an association between other chemotherapy agents and neurocognitive function. 

“This information,” Dr Krull said, “is essential for designing effective intervention to address the risk.”

“Methotrexate has contributed to historically high cure rates for childhood leukemia,” Dr Krull said. “While physicians may look for opportunities to reduce concentrations of the drug in the future, interventions are already in development to enhance executive function in patients on therapy as well as long-term childhood cancer survivors.”

The investigators reported their findings in JCO.

LONDON – Tumor necrosis factor may play a role in erosive hand osteoarthritis, and treatments such as etanercept that target this cytokine may help prevent progression of the condition, according to the results of two studies presented at the European Congress of Rheumatology.

In one of the studies, immunoscintigraphic detection of radiolabeled certolizumab pegol was used to show that tumor necrosis factor (TNF) was present in swollen finger joints. In another study, researchers looked to see if treatment with etanercept would have any specific effects on the joints of patients with erosive hand osteoarthritis (OA) and performed a separate analysis of the potential effect on synovitis and the effect on bone marrow lesions.

“We previously had the idea that TNF is an important cytokine in the pathogenesis of erosive [hand] osteoarthritis; but there have been no animal studies, and it’s very difficult to take biopsies or fluid aspiration from these small finger joints,” Dr. Ruth Wittoek, a staff rheumatologist at Ghent University Hospital in Belgium and a coauthor of all three studies, explained in a precongress interview. “We needed to look for other possibilities to really identify the presence of TNF in those affected joints.”

Dr. Wittoek and her associates used immunoscintigraphy to take static images of both hands of five patients with erosive OA immediately (less than 15 minutes) after administration of radiolabeled certolizumab pegol (early phase) and 4-6 hours following the injection (late phase).

The patients studied had erosive OA for a median of 8.4 years, and their median age was 55.6 years. All patients underwent clinical examination for presence of tenderness and palpable swelling of the joints and ultrasound 1 day prior to undergoing immunoscintigraphy.

All 18 interphalangeal (IP) finger joints were scored according to the anatomical phase scoring system on x-ray, and 90 IP finger joints were studied in total. The uptake of radiolabeled certolizumab pegol was semiquantitatively described as being absent, weak, or strong.

During the early phase following administration, uptake of the radiolabeled TNF inhibitor was seen in seven (7.8%) joints, although the uptake was described as weak in all cases. The radiolabeled TNF inhibitor was seen in 24 (26.7%) joints during the late phase following administration, with five instances described as strong uptake and the remaining 19 instances being weak uptake. No uptake of the radiolabeled TNF inhibitor was seen in metacarpophalangeal joints.

Uptake of the radiolabeled TNF inhibitor was linked to signs of disease activity, including tender, swollen, and radiographically active joints.

Late uptake was present in 12 (36.4%) of 33 tender joints and in 12 (21.1%) of 57 nontender joints (odds ratio, 2.1; 95% confidence interval, 0.8-5.6; P was nonsignificant).

The relationship was most pronounced with palpable joint swelling: Late uptake was present in 14 (61%) of 23 swollen joints and 10 (14.9%) of 67 nonswollen joints (OR, 8.9; 95% CI, 3.3-26.0; P less than .001).

Late uptake was present in 18 (29%) of 62 sonographically active joints (defined as any presence of effusion or synovial proliferation) but just 6 (21.4%) of 28 noninflamed joints (OR, 1.5; 95% CI, 0.5-4.3; P was nonsignificant).

Uptake of the radiolabeled TNF inhibitor was observed in all anatomical phases of erosive hand OA, Dr. Wittoek noted, but the strongest association was found during the final remodeling (R) phase.

“Soft-tissue swelling strongly correlated with uptake of certolizumab, meaning in these joints a lot of TNF was present,” Dr. Wittoek said. “These data further solidify the rationale for cytokine-directed therapies in erosive OA.”

Although the data provide proof of concept that TNF may be involved in erosive hand OA, the lack of a control tracer was noted as a limitation of the study after the investigator’s presentation. Dr. Wittoek conceded that it would be interesting to examine that in a future study.

So, if TNF is present, what effect does anti-TNF therapy have on the joints in erosive hand OA?

That question was addressed in a multicenter, double-blind, randomized, placebo-controlled trial involving 90 patients who were randomized to receive either 50 mg of subcutaneous etanercept weekly for 24 weeks, then 25 mg weekly for the remainder of 1 year (45 patients), or placebo (45 patients). Participants were a mean age of 60 years, 81% were women, and 96% fulfilled the American College of Rheumatology hand OA criteria.

“Synovial inflammation is often present in erosive hand OA; moreover, synovitis is associated with pain and with structural damage after around 2 and a half years,” the lead study author, Dr. Margreet Kloppenburg, a professor of rheumatology at Leiden University Medical Centre in the Netherlands, said in an interview.

“Therefore, we wanted to know whether blocking of synovial inflammation by a well-known drug such as etanercept would also have a positive effect on outcomes in erosive hand OA,” Dr. Kloppenburg explained.

The primary outcome measure was the level of OA pain assessed on a visual analog scale (VAS) at 24 weeks.

Secondary endpoints included assessment of hand function, quality of life, the number of tender joints, and grip strength after 4, 8, 12, 24, and 36 weeks, and after 1 year. Radiographic progression of IP joints was scored blindly at baseline, 24 weeks, and 1 year following the quantitative Ghent University Scoring System (GUSS). VAS pain was compared between treatment groups at 24 weeks and 1 year in intention-to-treat analyses.

Although etanercept was not superior to placebo on VAS pain at 24 weeks, it was superior to placebo both on pain and structural damage assessed by GUSS in the symptomatic and inflammatory patients who completed the study. The drug was especially effective in joints with signs of inflammation.

Overall, VAS pain in all patients decreased by 24.8 mm (95% CI, –29.2 to –20.5; P less than .001) at 24 weeks. In intention-to-treat analysis, differences in pain between the groups were in favor of etanercept but did not reach statistical significance. The per-protocol analysis of GUSS showed a mean difference in favor of etanercept, indicating more remodeling in the etanercept group.

Additional analyses showed an interaction between soft swelling/erythema and etanercept treatment on GUSS, resulting in a statistically significant (P less than .05) mean difference between the two treatment groups. More patients dropped out on placebo than on etanercept (six vs. three) because of inefficacy, whereas more dropped out on etanercept than on placebo (six vs. one) because of adverse effects.

“Synovial inflammation is an interesting target for treatment in OA patients with an inflammatory hand osteoarthritis phenotype,” Dr. Kloppenburg said.

A separate analysis of the same multicenter study suggests that etanercept is effective in inhibiting bone marrow lesions (BMLs) in patients with erosive hand OA.

The researchers studied 20 participants with symptomatic erosive OA with clinical and ultrasonographic signs of inflammation in at least one IP joint. The patients underwent contrast-enhanced MRI of the eight distal and proximal IP joints of one hand at baseline and 1 year. Images were scored for synovitis and BMLs (0-3 per joint, total score 0-24), blinded for patient characteristics.

Radiographs of the same hand were scored according to the Verbruggen-Veys system. Logistic regression was used to associate the presence of an MRI feature in a joint with being in an erosive versus nonerosive anatomical phase.

“Although erosive hand OA is a condition with a high disease burden, no disease-modifying treatments are available yet,” explained Féline Kroon, a PhD student in the department of rheumatology at Leiden University Medical Center in the Netherlands, in an interview. “Research to find a new form of therapy is partly hindered by our limited knowledge on the pathophysiology of the disease.”

However, “new imaging modalities like MRI enable us to study the pathophysiology of erosive OA more closely,” she said. “This study also gave us the unique opportunity to investigate whether anti-TNF, which is known to lead to clinical improvement and improvement of inflammatory lesions on MRI in other rheumatic diseases like rheumatoid arthritis, might also be effective in erosive OA.”

The presence of BMLs, but not synovitis, was associated with the presence of an erosive anatomical phase in a joint, and treatment with etanercept appeared to be effective in inhibiting these lesions. That suggests a role for TNF in the pathophysiology of erosive OA.

The inhibitory effect of etanercept on BMLs was more pronounced in IP joints with severe synovitis at baseline, suggesting that inflamed synovial tissue could be a source of TNF production in erosive OA.

The total synovitis score was similar at baseline and 1 year in both study groups. For BMLs, the median total score at baseline was 5.4 (range 2-9) and 7.0 (0-9) at 1 year in the placebo group, versus 4.5 (3-9) and 3.7 (0-8), respectively, in the etanercept group.

The presence of BMLs was associated with being in the erosive and remodeling anatomical phases of erosive hand OA. Synovitis was not associated with those phases.

“We think that TNF-alpha plays a role in the pathophysiology of erosive OA via an effect on the subchondral bone,” Ms. Kroon said. “Because we saw that the beneficial effect of etanercept on BMLs was more pronounced in joints with synovitis at baseline, we think that, in an inflamed synovial hand joint, an interaction takes place between synovium and subchondral bone, which could be influenced by blocking TNF.”

Pfizer and UCB supported the investigator-initiated studies and provided the study drugs. Dr. Kloppenburg has received lecturing, consultancy, and investigator fees or grants from AbbVie, APPROACH, GlaxoSmithKline, Levicept, Pfizer, Servier, and UCB, all paid to her institution. All other authors declared no conflicts of interests.

[email protected]

LONDON – Tumor necrosis factor may play a role in erosive hand osteoarthritis, and treatments such as etanercept that target this cytokine may help prevent progression of the condition, according to the results of two studies presented at the European Congress of Rheumatology.

In one of the studies, immunoscintigraphic detection of radiolabeled certolizumab pegol was used to show that tumor necrosis factor (TNF) was present in swollen finger joints. In another study, researchers looked to see if treatment with etanercept would have any specific effects on the joints of patients with erosive hand osteoarthritis (OA) and performed a separate analysis of the potential effect on synovitis and the effect on bone marrow lesions.

“We previously had the idea that TNF is an important cytokine in the pathogenesis of erosive [hand] osteoarthritis; but there have been no animal studies, and it’s very difficult to take biopsies or fluid aspiration from these small finger joints,” Dr. Ruth Wittoek, a staff rheumatologist at Ghent University Hospital in Belgium and a coauthor of all three studies, explained in a precongress interview. “We needed to look for other possibilities to really identify the presence of TNF in those affected joints.”

Dr. Wittoek and her associates used immunoscintigraphy to take static images of both hands of five patients with erosive OA immediately (less than 15 minutes) after administration of radiolabeled certolizumab pegol (early phase) and 4-6 hours following the injection (late phase).

The patients studied had erosive OA for a median of 8.4 years, and their median age was 55.6 years. All patients underwent clinical examination for presence of tenderness and palpable swelling of the joints and ultrasound 1 day prior to undergoing immunoscintigraphy.

All 18 interphalangeal (IP) finger joints were scored according to the anatomical phase scoring system on x-ray, and 90 IP finger joints were studied in total. The uptake of radiolabeled certolizumab pegol was semiquantitatively described as being absent, weak, or strong.

During the early phase following administration, uptake of the radiolabeled TNF inhibitor was seen in seven (7.8%) joints, although the uptake was described as weak in all cases. The radiolabeled TNF inhibitor was seen in 24 (26.7%) joints during the late phase following administration, with five instances described as strong uptake and the remaining 19 instances being weak uptake. No uptake of the radiolabeled TNF inhibitor was seen in metacarpophalangeal joints.

Uptake of the radiolabeled TNF inhibitor was linked to signs of disease activity, including tender, swollen, and radiographically active joints.

Late uptake was present in 12 (36.4%) of 33 tender joints and in 12 (21.1%) of 57 nontender joints (odds ratio, 2.1; 95% confidence interval, 0.8-5.6; P was nonsignificant).

The relationship was most pronounced with palpable joint swelling: Late uptake was present in 14 (61%) of 23 swollen joints and 10 (14.9%) of 67 nonswollen joints (OR, 8.9; 95% CI, 3.3-26.0; P less than .001).

Late uptake was present in 18 (29%) of 62 sonographically active joints (defined as any presence of effusion or synovial proliferation) but just 6 (21.4%) of 28 noninflamed joints (OR, 1.5; 95% CI, 0.5-4.3; P was nonsignificant).

Uptake of the radiolabeled TNF inhibitor was observed in all anatomical phases of erosive hand OA, Dr. Wittoek noted, but the strongest association was found during the final remodeling (R) phase.

“Soft-tissue swelling strongly correlated with uptake of certolizumab, meaning in these joints a lot of TNF was present,” Dr. Wittoek said. “These data further solidify the rationale for cytokine-directed therapies in erosive OA.”

Although the data provide proof of concept that TNF may be involved in erosive hand OA, the lack of a control tracer was noted as a limitation of the study after the investigator’s presentation. Dr. Wittoek conceded that it would be interesting to examine that in a future study.

So, if TNF is present, what effect does anti-TNF therapy have on the joints in erosive hand OA?

That question was addressed in a multicenter, double-blind, randomized, placebo-controlled trial involving 90 patients who were randomized to receive either 50 mg of subcutaneous etanercept weekly for 24 weeks, then 25 mg weekly for the remainder of 1 year (45 patients), or placebo (45 patients). Participants were a mean age of 60 years, 81% were women, and 96% fulfilled the American College of Rheumatology hand OA criteria.

“Synovial inflammation is often present in erosive hand OA; moreover, synovitis is associated with pain and with structural damage after around 2 and a half years,” the lead study author, Dr. Margreet Kloppenburg, a professor of rheumatology at Leiden University Medical Centre in the Netherlands, said in an interview.

“Therefore, we wanted to know whether blocking of synovial inflammation by a well-known drug such as etanercept would also have a positive effect on outcomes in erosive hand OA,” Dr. Kloppenburg explained.

The primary outcome measure was the level of OA pain assessed on a visual analog scale (VAS) at 24 weeks.

Secondary endpoints included assessment of hand function, quality of life, the number of tender joints, and grip strength after 4, 8, 12, 24, and 36 weeks, and after 1 year. Radiographic progression of IP joints was scored blindly at baseline, 24 weeks, and 1 year following the quantitative Ghent University Scoring System (GUSS). VAS pain was compared between treatment groups at 24 weeks and 1 year in intention-to-treat analyses.

Although etanercept was not superior to placebo on VAS pain at 24 weeks, it was superior to placebo both on pain and structural damage assessed by GUSS in the symptomatic and inflammatory patients who completed the study. The drug was especially effective in joints with signs of inflammation.

Overall, VAS pain in all patients decreased by 24.8 mm (95% CI, –29.2 to –20.5; P less than .001) at 24 weeks. In intention-to-treat analysis, differences in pain between the groups were in favor of etanercept but did not reach statistical significance. The per-protocol analysis of GUSS showed a mean difference in favor of etanercept, indicating more remodeling in the etanercept group.

Additional analyses showed an interaction between soft swelling/erythema and etanercept treatment on GUSS, resulting in a statistically significant (P less than .05) mean difference between the two treatment groups. More patients dropped out on placebo than on etanercept (six vs. three) because of inefficacy, whereas more dropped out on etanercept than on placebo (six vs. one) because of adverse effects.

“Synovial inflammation is an interesting target for treatment in OA patients with an inflammatory hand osteoarthritis phenotype,” Dr. Kloppenburg said.

A separate analysis of the same multicenter study suggests that etanercept is effective in inhibiting bone marrow lesions (BMLs) in patients with erosive hand OA.

The researchers studied 20 participants with symptomatic erosive OA with clinical and ultrasonographic signs of inflammation in at least one IP joint. The patients underwent contrast-enhanced MRI of the eight distal and proximal IP joints of one hand at baseline and 1 year. Images were scored for synovitis and BMLs (0-3 per joint, total score 0-24), blinded for patient characteristics.

Radiographs of the same hand were scored according to the Verbruggen-Veys system. Logistic regression was used to associate the presence of an MRI feature in a joint with being in an erosive versus nonerosive anatomical phase.

“Although erosive hand OA is a condition with a high disease burden, no disease-modifying treatments are available yet,” explained Féline Kroon, a PhD student in the department of rheumatology at Leiden University Medical Center in the Netherlands, in an interview. “Research to find a new form of therapy is partly hindered by our limited knowledge on the pathophysiology of the disease.”

However, “new imaging modalities like MRI enable us to study the pathophysiology of erosive OA more closely,” she said. “This study also gave us the unique opportunity to investigate whether anti-TNF, which is known to lead to clinical improvement and improvement of inflammatory lesions on MRI in other rheumatic diseases like rheumatoid arthritis, might also be effective in erosive OA.”

The presence of BMLs, but not synovitis, was associated with the presence of an erosive anatomical phase in a joint, and treatment with etanercept appeared to be effective in inhibiting these lesions. That suggests a role for TNF in the pathophysiology of erosive OA.

The inhibitory effect of etanercept on BMLs was more pronounced in IP joints with severe synovitis at baseline, suggesting that inflamed synovial tissue could be a source of TNF production in erosive OA.

The total synovitis score was similar at baseline and 1 year in both study groups. For BMLs, the median total score at baseline was 5.4 (range 2-9) and 7.0 (0-9) at 1 year in the placebo group, versus 4.5 (3-9) and 3.7 (0-8), respectively, in the etanercept group.

The presence of BMLs was associated with being in the erosive and remodeling anatomical phases of erosive hand OA. Synovitis was not associated with those phases.

“We think that TNF-alpha plays a role in the pathophysiology of erosive OA via an effect on the subchondral bone,” Ms. Kroon said. “Because we saw that the beneficial effect of etanercept on BMLs was more pronounced in joints with synovitis at baseline, we think that, in an inflamed synovial hand joint, an interaction takes place between synovium and subchondral bone, which could be influenced by blocking TNF.”

Pfizer and UCB supported the investigator-initiated studies and provided the study drugs. Dr. Kloppenburg has received lecturing, consultancy, and investigator fees or grants from AbbVie, APPROACH, GlaxoSmithKline, Levicept, Pfizer, Servier, and UCB, all paid to her institution. All other authors declared no conflicts of interests.

[email protected]

LONDON – Tumor necrosis factor may play a role in erosive hand osteoarthritis, and treatments such as etanercept that target this cytokine may help prevent progression of the condition, according to the results of two studies presented at the European Congress of Rheumatology.

In one of the studies, immunoscintigraphic detection of radiolabeled certolizumab pegol was used to show that tumor necrosis factor (TNF) was present in swollen finger joints. In another study, researchers looked to see if treatment with etanercept would have any specific effects on the joints of patients with erosive hand osteoarthritis (OA) and performed a separate analysis of the potential effect on synovitis and the effect on bone marrow lesions.

“We previously had the idea that TNF is an important cytokine in the pathogenesis of erosive [hand] osteoarthritis; but there have been no animal studies, and it’s very difficult to take biopsies or fluid aspiration from these small finger joints,” Dr. Ruth Wittoek, a staff rheumatologist at Ghent University Hospital in Belgium and a coauthor of all three studies, explained in a precongress interview. “We needed to look for other possibilities to really identify the presence of TNF in those affected joints.”

Dr. Wittoek and her associates used immunoscintigraphy to take static images of both hands of five patients with erosive OA immediately (less than 15 minutes) after administration of radiolabeled certolizumab pegol (early phase) and 4-6 hours following the injection (late phase).

The patients studied had erosive OA for a median of 8.4 years, and their median age was 55.6 years. All patients underwent clinical examination for presence of tenderness and palpable swelling of the joints and ultrasound 1 day prior to undergoing immunoscintigraphy.

All 18 interphalangeal (IP) finger joints were scored according to the anatomical phase scoring system on x-ray, and 90 IP finger joints were studied in total. The uptake of radiolabeled certolizumab pegol was semiquantitatively described as being absent, weak, or strong.

During the early phase following administration, uptake of the radiolabeled TNF inhibitor was seen in seven (7.8%) joints, although the uptake was described as weak in all cases. The radiolabeled TNF inhibitor was seen in 24 (26.7%) joints during the late phase following administration, with five instances described as strong uptake and the remaining 19 instances being weak uptake. No uptake of the radiolabeled TNF inhibitor was seen in metacarpophalangeal joints.

Uptake of the radiolabeled TNF inhibitor was linked to signs of disease activity, including tender, swollen, and radiographically active joints.

Late uptake was present in 12 (36.4%) of 33 tender joints and in 12 (21.1%) of 57 nontender joints (odds ratio, 2.1; 95% confidence interval, 0.8-5.6; P was nonsignificant).

The relationship was most pronounced with palpable joint swelling: Late uptake was present in 14 (61%) of 23 swollen joints and 10 (14.9%) of 67 nonswollen joints (OR, 8.9; 95% CI, 3.3-26.0; P less than .001).

Late uptake was present in 18 (29%) of 62 sonographically active joints (defined as any presence of effusion or synovial proliferation) but just 6 (21.4%) of 28 noninflamed joints (OR, 1.5; 95% CI, 0.5-4.3; P was nonsignificant).

Uptake of the radiolabeled TNF inhibitor was observed in all anatomical phases of erosive hand OA, Dr. Wittoek noted, but the strongest association was found during the final remodeling (R) phase.

“Soft-tissue swelling strongly correlated with uptake of certolizumab, meaning in these joints a lot of TNF was present,” Dr. Wittoek said. “These data further solidify the rationale for cytokine-directed therapies in erosive OA.”

Although the data provide proof of concept that TNF may be involved in erosive hand OA, the lack of a control tracer was noted as a limitation of the study after the investigator’s presentation. Dr. Wittoek conceded that it would be interesting to examine that in a future study.

So, if TNF is present, what effect does anti-TNF therapy have on the joints in erosive hand OA?

That question was addressed in a multicenter, double-blind, randomized, placebo-controlled trial involving 90 patients who were randomized to receive either 50 mg of subcutaneous etanercept weekly for 24 weeks, then 25 mg weekly for the remainder of 1 year (45 patients), or placebo (45 patients). Participants were a mean age of 60 years, 81% were women, and 96% fulfilled the American College of Rheumatology hand OA criteria.

“Synovial inflammation is often present in erosive hand OA; moreover, synovitis is associated with pain and with structural damage after around 2 and a half years,” the lead study author, Dr. Margreet Kloppenburg, a professor of rheumatology at Leiden University Medical Centre in the Netherlands, said in an interview.

“Therefore, we wanted to know whether blocking of synovial inflammation by a well-known drug such as etanercept would also have a positive effect on outcomes in erosive hand OA,” Dr. Kloppenburg explained.

The primary outcome measure was the level of OA pain assessed on a visual analog scale (VAS) at 24 weeks.

Secondary endpoints included assessment of hand function, quality of life, the number of tender joints, and grip strength after 4, 8, 12, 24, and 36 weeks, and after 1 year. Radiographic progression of IP joints was scored blindly at baseline, 24 weeks, and 1 year following the quantitative Ghent University Scoring System (GUSS). VAS pain was compared between treatment groups at 24 weeks and 1 year in intention-to-treat analyses.

Although etanercept was not superior to placebo on VAS pain at 24 weeks, it was superior to placebo both on pain and structural damage assessed by GUSS in the symptomatic and inflammatory patients who completed the study. The drug was especially effective in joints with signs of inflammation.

Overall, VAS pain in all patients decreased by 24.8 mm (95% CI, –29.2 to –20.5; P less than .001) at 24 weeks. In intention-to-treat analysis, differences in pain between the groups were in favor of etanercept but did not reach statistical significance. The per-protocol analysis of GUSS showed a mean difference in favor of etanercept, indicating more remodeling in the etanercept group.

Additional analyses showed an interaction between soft swelling/erythema and etanercept treatment on GUSS, resulting in a statistically significant (P less than .05) mean difference between the two treatment groups. More patients dropped out on placebo than on etanercept (six vs. three) because of inefficacy, whereas more dropped out on etanercept than on placebo (six vs. one) because of adverse effects.

“Synovial inflammation is an interesting target for treatment in OA patients with an inflammatory hand osteoarthritis phenotype,” Dr. Kloppenburg said.

A separate analysis of the same multicenter study suggests that etanercept is effective in inhibiting bone marrow lesions (BMLs) in patients with erosive hand OA.

The researchers studied 20 participants with symptomatic erosive OA with clinical and ultrasonographic signs of inflammation in at least one IP joint. The patients underwent contrast-enhanced MRI of the eight distal and proximal IP joints of one hand at baseline and 1 year. Images were scored for synovitis and BMLs (0-3 per joint, total score 0-24), blinded for patient characteristics.

Radiographs of the same hand were scored according to the Verbruggen-Veys system. Logistic regression was used to associate the presence of an MRI feature in a joint with being in an erosive versus nonerosive anatomical phase.

“Although erosive hand OA is a condition with a high disease burden, no disease-modifying treatments are available yet,” explained Féline Kroon, a PhD student in the department of rheumatology at Leiden University Medical Center in the Netherlands, in an interview. “Research to find a new form of therapy is partly hindered by our limited knowledge on the pathophysiology of the disease.”

However, “new imaging modalities like MRI enable us to study the pathophysiology of erosive OA more closely,” she said. “This study also gave us the unique opportunity to investigate whether anti-TNF, which is known to lead to clinical improvement and improvement of inflammatory lesions on MRI in other rheumatic diseases like rheumatoid arthritis, might also be effective in erosive OA.”

The presence of BMLs, but not synovitis, was associated with the presence of an erosive anatomical phase in a joint, and treatment with etanercept appeared to be effective in inhibiting these lesions. That suggests a role for TNF in the pathophysiology of erosive OA.

The inhibitory effect of etanercept on BMLs was more pronounced in IP joints with severe synovitis at baseline, suggesting that inflamed synovial tissue could be a source of TNF production in erosive OA.

The total synovitis score was similar at baseline and 1 year in both study groups. For BMLs, the median total score at baseline was 5.4 (range 2-9) and 7.0 (0-9) at 1 year in the placebo group, versus 4.5 (3-9) and 3.7 (0-8), respectively, in the etanercept group.

The presence of BMLs was associated with being in the erosive and remodeling anatomical phases of erosive hand OA. Synovitis was not associated with those phases.

“We think that TNF-alpha plays a role in the pathophysiology of erosive OA via an effect on the subchondral bone,” Ms. Kroon said. “Because we saw that the beneficial effect of etanercept on BMLs was more pronounced in joints with synovitis at baseline, we think that, in an inflamed synovial hand joint, an interaction takes place between synovium and subchondral bone, which could be influenced by blocking TNF.”

Pfizer and UCB supported the investigator-initiated studies and provided the study drugs. Dr. Kloppenburg has received lecturing, consultancy, and investigator fees or grants from AbbVie, APPROACH, GlaxoSmithKline, Levicept, Pfizer, Servier, and UCB, all paid to her institution. All other authors declared no conflicts of interests.

[email protected]

Data from the latest National Youth Risk Behavior Survey show that although many harmful behaviors are declining among high school students across the United States, work still needs to be done to eliminate risks that linger and quell those starting to crop up.

“We are encouraged to see that high school students are making some better choices; unfortunately, [we] are also facing some big challenges,” Dr. Stephanie Zaza, director of the division of adolescent and school health at the Centers for Disease Control and Prevention, said June 9 during a teleconference.

More than 15,000 high school students – located in 37 states and 19 large, urban school districts – participated in the survey, which analyzed risk behaviors in key health and wellness categories. Smoking has decreased significantly since 1991, the inaugural year of the survey, dropping from 70% to 32% for students who had ever tried a cigarette. Hispanic males (37%) and students in 11th grade (38%) had the highest rates of cigarette use. However, e-cigarette use continues to be a growing issue, with 45% of high school students reporting having used an electronic vapor product at some point. This category includes not just e-cigarettes, but vape pipes and e-hookahs.

Opiate use also continues to be a challenging issue for public health, with 17% of high school students reporting that they have used a prescription drug despite not having a doctor’s prescription to use it. Those drugs include OxyContin (oxycodone), Percocet (acetaminophen/oxycodone), Vicodin (acetaminophen/hydrocodone), and codeine. Other problematic drugs among these students are the stimulants Adderall (dextroamphetamine plus amphetamine) and Ritalin (methylphenidate hydrochloride), and Xanax (alprazolam), a benzodiazepine. Males were more likely to use drugs without a prescription than female students were: 18% vs.16%, respectively.

Results related to interpersonal violence – such as schoolyard fighting and physical bullying – were “mixed,” according to Dr. Zaza. Students who had engaged in a physical fight in the last year registered 23%, a sharp decrease from the 42% logged in 1991; however, bullying rates continue to remain high, with 20% of students reporting being involved with physical bullying and 16% reporting involvement with cyberbullying in some capacity.

On a more positive note, students seem to be eating better, with dietary statistics looking increasingly optimistic. In particular, consumption of sugar-heavy drinks and sodas dropped significantly from 27% in 2013 to 20% last year. But Dr. Zaza warned that dietary improvements are offset by continued sedentary lifestyles. Although TV watching has declined, it has been effectively replaced by increased time in front of computers and video games; use of a computer for tasks unrelated to school for more than 3 hours daily rose, from 22% in 2003 to 42% in 2015.

The percentage of sexually active high school students – those who have had sexual intercourse in the 3 months before participating in the survey – has dropped to 30%, from 38% in 1991. However, despite this, condom use among sexually active high school students also declined, going from 63% in 2003 to 57% in 2015.

Also alarming is that 21% of sexually active students reported consuming drugs or alcohol before their last sexual encounter. Testing for HIV among sexually active high school student also has decreased, from 13% in 2013 to 10% in 2015.

A total of 42% of students reported texting or emailing while driving in the 30 days prior to taking the survey, which is steady with the data from 2013.

“There’s no single solution to improving health risk behaviors among high school students, and we can all collaborate to help address these health risks using interventions that are based on the best science available,” Dr. Zaza said. “We hope that public health professionals, educators, youth service providers, policy makers, and parents can use these data to guide their planning decisions, and help schools and communities reduce youth health risk behaviors.”

The CDC conducted and released the survey.

[email protected]

Data from the latest National Youth Risk Behavior Survey show that although many harmful behaviors are declining among high school students across the United States, work still needs to be done to eliminate risks that linger and quell those starting to crop up.

“We are encouraged to see that high school students are making some better choices; unfortunately, [we] are also facing some big challenges,” Dr. Stephanie Zaza, director of the division of adolescent and school health at the Centers for Disease Control and Prevention, said June 9 during a teleconference.

More than 15,000 high school students – located in 37 states and 19 large, urban school districts – participated in the survey, which analyzed risk behaviors in key health and wellness categories. Smoking has decreased significantly since 1991, the inaugural year of the survey, dropping from 70% to 32% for students who had ever tried a cigarette. Hispanic males (37%) and students in 11th grade (38%) had the highest rates of cigarette use. However, e-cigarette use continues to be a growing issue, with 45% of high school students reporting having used an electronic vapor product at some point. This category includes not just e-cigarettes, but vape pipes and e-hookahs.

Opiate use also continues to be a challenging issue for public health, with 17% of high school students reporting that they have used a prescription drug despite not having a doctor’s prescription to use it. Those drugs include OxyContin (oxycodone), Percocet (acetaminophen/oxycodone), Vicodin (acetaminophen/hydrocodone), and codeine. Other problematic drugs among these students are the stimulants Adderall (dextroamphetamine plus amphetamine) and Ritalin (methylphenidate hydrochloride), and Xanax (alprazolam), a benzodiazepine. Males were more likely to use drugs without a prescription than female students were: 18% vs.16%, respectively.

Results related to interpersonal violence – such as schoolyard fighting and physical bullying – were “mixed,” according to Dr. Zaza. Students who had engaged in a physical fight in the last year registered 23%, a sharp decrease from the 42% logged in 1991; however, bullying rates continue to remain high, with 20% of students reporting being involved with physical bullying and 16% reporting involvement with cyberbullying in some capacity.

On a more positive note, students seem to be eating better, with dietary statistics looking increasingly optimistic. In particular, consumption of sugar-heavy drinks and sodas dropped significantly from 27% in 2013 to 20% last year. But Dr. Zaza warned that dietary improvements are offset by continued sedentary lifestyles. Although TV watching has declined, it has been effectively replaced by increased time in front of computers and video games; use of a computer for tasks unrelated to school for more than 3 hours daily rose, from 22% in 2003 to 42% in 2015.

The percentage of sexually active high school students – those who have had sexual intercourse in the 3 months before participating in the survey – has dropped to 30%, from 38% in 1991. However, despite this, condom use among sexually active high school students also declined, going from 63% in 2003 to 57% in 2015.

Also alarming is that 21% of sexually active students reported consuming drugs or alcohol before their last sexual encounter. Testing for HIV among sexually active high school student also has decreased, from 13% in 2013 to 10% in 2015.

A total of 42% of students reported texting or emailing while driving in the 30 days prior to taking the survey, which is steady with the data from 2013.

“There’s no single solution to improving health risk behaviors among high school students, and we can all collaborate to help address these health risks using interventions that are based on the best science available,” Dr. Zaza said. “We hope that public health professionals, educators, youth service providers, policy makers, and parents can use these data to guide their planning decisions, and help schools and communities reduce youth health risk behaviors.”

The CDC conducted and released the survey.

[email protected]

Data from the latest National Youth Risk Behavior Survey show that although many harmful behaviors are declining among high school students across the United States, work still needs to be done to eliminate risks that linger and quell those starting to crop up.

“We are encouraged to see that high school students are making some better choices; unfortunately, [we] are also facing some big challenges,” Dr. Stephanie Zaza, director of the division of adolescent and school health at the Centers for Disease Control and Prevention, said June 9 during a teleconference.

More than 15,000 high school students – located in 37 states and 19 large, urban school districts – participated in the survey, which analyzed risk behaviors in key health and wellness categories. Smoking has decreased significantly since 1991, the inaugural year of the survey, dropping from 70% to 32% for students who had ever tried a cigarette. Hispanic males (37%) and students in 11th grade (38%) had the highest rates of cigarette use. However, e-cigarette use continues to be a growing issue, with 45% of high school students reporting having used an electronic vapor product at some point. This category includes not just e-cigarettes, but vape pipes and e-hookahs.

Opiate use also continues to be a challenging issue for public health, with 17% of high school students reporting that they have used a prescription drug despite not having a doctor’s prescription to use it. Those drugs include OxyContin (oxycodone), Percocet (acetaminophen/oxycodone), Vicodin (acetaminophen/hydrocodone), and codeine. Other problematic drugs among these students are the stimulants Adderall (dextroamphetamine plus amphetamine) and Ritalin (methylphenidate hydrochloride), and Xanax (alprazolam), a benzodiazepine. Males were more likely to use drugs without a prescription than female students were: 18% vs.16%, respectively.

Results related to interpersonal violence – such as schoolyard fighting and physical bullying – were “mixed,” according to Dr. Zaza. Students who had engaged in a physical fight in the last year registered 23%, a sharp decrease from the 42% logged in 1991; however, bullying rates continue to remain high, with 20% of students reporting being involved with physical bullying and 16% reporting involvement with cyberbullying in some capacity.

On a more positive note, students seem to be eating better, with dietary statistics looking increasingly optimistic. In particular, consumption of sugar-heavy drinks and sodas dropped significantly from 27% in 2013 to 20% last year. But Dr. Zaza warned that dietary improvements are offset by continued sedentary lifestyles. Although TV watching has declined, it has been effectively replaced by increased time in front of computers and video games; use of a computer for tasks unrelated to school for more than 3 hours daily rose, from 22% in 2003 to 42% in 2015.

The percentage of sexually active high school students – those who have had sexual intercourse in the 3 months before participating in the survey – has dropped to 30%, from 38% in 1991. However, despite this, condom use among sexually active high school students also declined, going from 63% in 2003 to 57% in 2015.

Also alarming is that 21% of sexually active students reported consuming drugs or alcohol before their last sexual encounter. Testing for HIV among sexually active high school student also has decreased, from 13% in 2013 to 10% in 2015.

A total of 42% of students reported texting or emailing while driving in the 30 days prior to taking the survey, which is steady with the data from 2013.

“There’s no single solution to improving health risk behaviors among high school students, and we can all collaborate to help address these health risks using interventions that are based on the best science available,” Dr. Zaza said. “We hope that public health professionals, educators, youth service providers, policy makers, and parents can use these data to guide their planning decisions, and help schools and communities reduce youth health risk behaviors.”

The CDC conducted and released the survey.

[email protected]

A 12-year-old girl presents for a well-child visit but is withdrawn, and her mother reports recent behavioral changes. Symptoms suggest a possible depressive disorder. The physician did not anticipate a mental health concern and is behind schedule. What are the next steps?

In this edition of Mental Health Consult, join our expert panelists for their analysis of this case, and their recommendations for assessing similar patients and addressing their mental health needs within the context of a busy primary care practice. Our panel includes Dr. David Pickar, a psychiatrist and former intramural research director for the National Institute of Mental Health; Dr. Lee Savio Beers of Children’s National Health System, Washington; and Dr. Lorenzo Norris, medical director of psychiatric and behavioral services at George Washington University Hospital, Washington.

“This is a case that … really gets at the heart of the idea of what is normal versus abnormal in terms of clinical depression,” says Dr. Norris. Watch the video to hear their perspectives on when and how to perform screening interventions, decide on referrals, handle emergent situations, and decide how practice models drive decisions and reimbursement.

Click here for a PDF of the case study.

[email protected]

A 12-year-old girl presents for a well-child visit but is withdrawn, and her mother reports recent behavioral changes. Symptoms suggest a possible depressive disorder. The physician did not anticipate a mental health concern and is behind schedule. What are the next steps?

In this edition of Mental Health Consult, join our expert panelists for their analysis of this case, and their recommendations for assessing similar patients and addressing their mental health needs within the context of a busy primary care practice. Our panel includes Dr. David Pickar, a psychiatrist and former intramural research director for the National Institute of Mental Health; Dr. Lee Savio Beers of Children’s National Health System, Washington; and Dr. Lorenzo Norris, medical director of psychiatric and behavioral services at George Washington University Hospital, Washington.

“This is a case that … really gets at the heart of the idea of what is normal versus abnormal in terms of clinical depression,” says Dr. Norris. Watch the video to hear their perspectives on when and how to perform screening interventions, decide on referrals, handle emergent situations, and decide how practice models drive decisions and reimbursement.

Click here for a PDF of the case study.

[email protected]

A 12-year-old girl presents for a well-child visit but is withdrawn, and her mother reports recent behavioral changes. Symptoms suggest a possible depressive disorder. The physician did not anticipate a mental health concern and is behind schedule. What are the next steps?

In this edition of Mental Health Consult, join our expert panelists for their analysis of this case, and their recommendations for assessing similar patients and addressing their mental health needs within the context of a busy primary care practice. Our panel includes Dr. David Pickar, a psychiatrist and former intramural research director for the National Institute of Mental Health; Dr. Lee Savio Beers of Children’s National Health System, Washington; and Dr. Lorenzo Norris, medical director of psychiatric and behavioral services at George Washington University Hospital, Washington.

“This is a case that … really gets at the heart of the idea of what is normal versus abnormal in terms of clinical depression,” says Dr. Norris. Watch the video to hear their perspectives on when and how to perform screening interventions, decide on referrals, handle emergent situations, and decide how practice models drive decisions and reimbursement.

Click here for a PDF of the case study.

[email protected]

San Francisco – Same day discharge is generally safe after cardioverter defibrillator implantation for primary prevention, but it doesn’t save money.

Furthermore, guidelines are needed to standardize the practice as it becomes increasingly common in the United States, according to a 25-site investigation.

After implantable cardioverter defibrillator (ICD) procedures, patients were monitored for 3-4 hours, and their devices were checked for proper functioning; 129 patients who were stable at that point were randomized to early discharge and 136 to next day discharge (NDD).

The overall 30-day procedural complication rate was 3.1% in the same day discharge (SDD) group and 1.6% in the NDD group, a nonsignificant difference (P = .37). Three patients in the SDD group developed hematomas that resolved on their own, and one had a cardiac perforation. One NDD patient dislodged a lead and another developed an infection. There were no differences in quality of life measures between the two groups at 30 days.

However, there were also no differences in procedural and perioperative direct costs, which was surprising because saving money is a major driver of SDD, and the most expensive part of ICD implantation is the first 24 hours. Direct per-patient medical costs in the study – estimated by applying hospital cost-to-charge ratios to the Medicare-reported charge – were $31,771 for SDD and $30,437 for NDD, but NDD was more expensive than SDD at several sites. The investigators suspect a flaw in their analysis related to the opaque nature of hospital accounting, and plan to look into the matter further with modeling to identify savings opportunities with SDD.

“We can insert ICDs on an outpatient basis, but this study will be difficult to replicate because clinical practice is moving towards SDD. In view of this, we think professional societies should be thinking of standardizing criteria for SDD; guidelines would help with the adoption of this approach. There are clinicians who are astute and have great clinical judgment, but there are others who need a scoring system. We believe that by using the 270,000 patients in the [American College of Cardiology’s ICD Registry], there is the ability to identify patients who have low periprocedural risk,” said lead investigator Dr. Ranjit Suri, a cardiologist at Mt. Sinai Hospital in New York.

The study excluded patients receiving an ICD for secondary prevention, as well as those on periprocedural heparin and patients who were pacemaker dependent. SDD seemed safe otherwise, but it’s unknown “if our concept of low risk is acceptable to all implanting physicians,” Dr. Suri said at the annual scientific sessions of the Heart Rhythm Society.

The study groups were well matched. About 75% in each arm were men, and ischemic cardiomyopathy was the leading ICD indication. Patients were amenable to the idea of SDD; the advent of remote monitoring “adds a certain sense of safety” for both patients and physicians, he said.

Dr. Suri is a speaker for Boehringer Ingelheim and St. Jude Medical. He is also a consultant for Biosense Webster and Zoll, and receives research funding from St. Jude.

[email protected]

San Francisco – Same day discharge is generally safe after cardioverter defibrillator implantation for primary prevention, but it doesn’t save money.

Furthermore, guidelines are needed to standardize the practice as it becomes increasingly common in the United States, according to a 25-site investigation.

After implantable cardioverter defibrillator (ICD) procedures, patients were monitored for 3-4 hours, and their devices were checked for proper functioning; 129 patients who were stable at that point were randomized to early discharge and 136 to next day discharge (NDD).

The overall 30-day procedural complication rate was 3.1% in the same day discharge (SDD) group and 1.6% in the NDD group, a nonsignificant difference (P = .37). Three patients in the SDD group developed hematomas that resolved on their own, and one had a cardiac perforation. One NDD patient dislodged a lead and another developed an infection. There were no differences in quality of life measures between the two groups at 30 days.

However, there were also no differences in procedural and perioperative direct costs, which was surprising because saving money is a major driver of SDD, and the most expensive part of ICD implantation is the first 24 hours. Direct per-patient medical costs in the study – estimated by applying hospital cost-to-charge ratios to the Medicare-reported charge – were $31,771 for SDD and $30,437 for NDD, but NDD was more expensive than SDD at several sites. The investigators suspect a flaw in their analysis related to the opaque nature of hospital accounting, and plan to look into the matter further with modeling to identify savings opportunities with SDD.

“We can insert ICDs on an outpatient basis, but this study will be difficult to replicate because clinical practice is moving towards SDD. In view of this, we think professional societies should be thinking of standardizing criteria for SDD; guidelines would help with the adoption of this approach. There are clinicians who are astute and have great clinical judgment, but there are others who need a scoring system. We believe that by using the 270,000 patients in the [American College of Cardiology’s ICD Registry], there is the ability to identify patients who have low periprocedural risk,” said lead investigator Dr. Ranjit Suri, a cardiologist at Mt. Sinai Hospital in New York.

The study excluded patients receiving an ICD for secondary prevention, as well as those on periprocedural heparin and patients who were pacemaker dependent. SDD seemed safe otherwise, but it’s unknown “if our concept of low risk is acceptable to all implanting physicians,” Dr. Suri said at the annual scientific sessions of the Heart Rhythm Society.

The study groups were well matched. About 75% in each arm were men, and ischemic cardiomyopathy was the leading ICD indication. Patients were amenable to the idea of SDD; the advent of remote monitoring “adds a certain sense of safety” for both patients and physicians, he said.

Dr. Suri is a speaker for Boehringer Ingelheim and St. Jude Medical. He is also a consultant for Biosense Webster and Zoll, and receives research funding from St. Jude.

[email protected]

San Francisco – Same day discharge is generally safe after cardioverter defibrillator implantation for primary prevention, but it doesn’t save money.

Furthermore, guidelines are needed to standardize the practice as it becomes increasingly common in the United States, according to a 25-site investigation.

After implantable cardioverter defibrillator (ICD) procedures, patients were monitored for 3-4 hours, and their devices were checked for proper functioning; 129 patients who were stable at that point were randomized to early discharge and 136 to next day discharge (NDD).

The overall 30-day procedural complication rate was 3.1% in the same day discharge (SDD) group and 1.6% in the NDD group, a nonsignificant difference (P = .37). Three patients in the SDD group developed hematomas that resolved on their own, and one had a cardiac perforation. One NDD patient dislodged a lead and another developed an infection. There were no differences in quality of life measures between the two groups at 30 days.

However, there were also no differences in procedural and perioperative direct costs, which was surprising because saving money is a major driver of SDD, and the most expensive part of ICD implantation is the first 24 hours. Direct per-patient medical costs in the study – estimated by applying hospital cost-to-charge ratios to the Medicare-reported charge – were $31,771 for SDD and $30,437 for NDD, but NDD was more expensive than SDD at several sites. The investigators suspect a flaw in their analysis related to the opaque nature of hospital accounting, and plan to look into the matter further with modeling to identify savings opportunities with SDD.

“We can insert ICDs on an outpatient basis, but this study will be difficult to replicate because clinical practice is moving towards SDD. In view of this, we think professional societies should be thinking of standardizing criteria for SDD; guidelines would help with the adoption of this approach. There are clinicians who are astute and have great clinical judgment, but there are others who need a scoring system. We believe that by using the 270,000 patients in the [American College of Cardiology’s ICD Registry], there is the ability to identify patients who have low periprocedural risk,” said lead investigator Dr. Ranjit Suri, a cardiologist at Mt. Sinai Hospital in New York.

The study excluded patients receiving an ICD for secondary prevention, as well as those on periprocedural heparin and patients who were pacemaker dependent. SDD seemed safe otherwise, but it’s unknown “if our concept of low risk is acceptable to all implanting physicians,” Dr. Suri said at the annual scientific sessions of the Heart Rhythm Society.

The study groups were well matched. About 75% in each arm were men, and ischemic cardiomyopathy was the leading ICD indication. Patients were amenable to the idea of SDD; the advent of remote monitoring “adds a certain sense of safety” for both patients and physicians, he said.

Dr. Suri is a speaker for Boehringer Ingelheim and St. Jude Medical. He is also a consultant for Biosense Webster and Zoll, and receives research funding from St. Jude.

[email protected]

This year’s Lifetime Achievement Award winner is called many things by his many nominators: quadruple hitter, visionary, mentor, revolutionary, unsurpassed, profoundly effective. But one thing is mentioned by all.

“Everybody,” they say, “calls him Jack.” That may be because Dr. Jack Cronenwett is not just a legend among SVS members, but he is also unassuming.

“Jack is one of the kindest and most humble person that you could meet,” said Dr. Marc L. Schermerhorn. “I was immediately surprised when I arrived at Dartmouth as a vascular fellow and heard him say, ‘Call me Jack.’ ”

Of Dr. Cronenwett’s – excuse us – Jack’s major achievements, the first was his work at Dartmouth-Hitchcock Medical Center.

In the 1980s, Dartmouth had a relatively small, little-known division of vascular surgery, and Jack was its first vascular surgeon. “He has trained and recruited the entire faculty and turned it into a powerhouse, a division of vascular surgery that has national and international recognition,” wrote Dr. Jens Eldrup-Jorgensen in his nomination.

In addition, Jack was largely responsible for the development at Dartmouth of a new vascular surgery training paradigm – the 0+5 residency. “He had the first program and was instrumental in making this type of program a possibility at the board level,” Dr. Schermerhorn wrote.

Getting a 0+5 program approved by the American Board of Surgery was an almost insurmountable hurdle.

“From my perspective,” said Jack, “it was all about training. We were advocating for a concept. You didn’t need to have full general surgery training in order to become a vascular surgeon. It was inefficient. We needed to be more focused. We couldn’t expand training every time a new procedure came along and still think that these residents needed to know how to do breast surgery.”

“Many of us work in institutions or divisions where we simply had to carry on what had been started by others,” noted Dr. Richard Cambria. “That was not the case at Dartmouth, where the present status of that outstanding vascular surgery division can be traced to Jack Cronenwett.”

The experience of building a program and expanding the processes of a vascular residency program seems to have whetted Jack’s appetite for leadership and educational excellence.

After the millennium, Jack’s legacy mushroomed with these outstanding achievements:

• 2002 – Spearheaded the Vascular Study Group of New England, a regional quality outcomes registry, which became the model for the future Vascular Quality Initiative

• 2003 – Took the reins of SVS as president and, with Dr. Tom Riles, then president of the American Association for Vascular Surgery (AAVS), convinced these organizations to merge and create an independent administrative office in Chicago, creating today’s more inclusive SVS.

• 2003-2008 – Was senior co-editor of the Journal of Vascular Surgery with Dr. James Seeger.

• 2010, 2014 – Was co-editor of the 7th and 8th editions of Rutherford’s Vascular Surgery textbook with Dr. K. Wayne Johnston.

• 2011 – Helped launch the SVS-PSO as an official new entity and has served as medical director since.

The Vascular Study Group of New England: This now well-known quality improvement registry was partially modeled after the Northern New England Cardiovascular Disease Study Group. “It was not just a copycat of NNECVDSG,” noted Dr. Eldrup-Jorgensen. “Biannual regional meetings were developed to promote quality improvement, which is somewhat uncommon for a registry.”

The organization grew and earned the attention of other centers around the country and the world. Under the umbrella of the SVS, the study group opened its membership and renamed itself the Vascular Quality Initiative, which today has 375 centers and a multidisciplinary membership that includes cardiologists and radiologists.

Vascular Quality Initiative: The huge success of the VQI, Dr. Jorgensen added, “required not only wisdom and vision, but also great judgment and the ability to work collaboratively and collegially.”

“Some of us may now take it for granted,” said Dr. Anton Sidawy, “but those of us who were involved in the discussions about VQI remember the endless night calls that we spent listening to Jack making various arguments about why the Society should invest in such a program. He actually had the plan completely conceived, describing the details of the regional concept used currently by VQI. I also remember the many meetings during VAM to discuss the program. Jack had the vision, the persistence and the details to be able to convince the SVS leadership to adopt it. We did, and as they say, the rest is history.”

President of SVS: While serving as SVS president, Jack worked with Dr. Tom Riles to push for the merger of two vascular societies, the SVS and the AAVS, into today’s Society for Vascular Surgery.

Senior co-editor, Journal of Vascular Surgery: As co-editor from 2003-2008, Jack has been recognized for leading significant changes that improved the content, quality and impact of the publication.

“Jack’s tenure on the Journal is when the number of submissions began to accelerate, exceeding a thousand per year,” recalled SVS President Dr. Bruce A. Perler. “He also started a program at the annual meeting to teach reviewers.”

He also served as a senior editor for recent editions of Rutherford’s Vascular Surgery textbook. The modern understanding of the pathophysiology and surgical decision-making surrounding the management of aortoiliac occlusive and infrarenal aortic aneurysm disease is profoundly influenced by his early work. His early studies of actuarial survival after aortic aneurysm surgery and cost effectiveness of asymptomatic carotid endarterectomy have inspired a generation of researchers.

A prolific writer and publisher himself, Jack has published more than 200 peer-reviewed journal articles, contributed chapters to more than 50 books, co-edited 14 books, delivered more than 300 invited presentations, and made nearly 200 peer-reviewed presentations at regional and national meetings.

In response to receiving this award, Jack expressed profound gratitude to his colleagues in the SVS for this recognition. “To me, this should really be called the SVS Lifetime ‘Opportunity’ Award. I have been afforded so many opportunities by the SVS during my life, which are only exceeded by the great number of close friendships that I have developed through the SVS. This has been a privilege and source of great gratification for me throughout my career.”

Among all his nominators and their excellent, thorough and effusive recommendations, Dr. Larry Kraiss summed it up as well as anyone: “Jack’s contributions outside of the VQI would make him a very strong candidate for the Lifetime Achievement Award. When you credit him with the VQI and its long-term positive impact on the SVS, I think he is a slam dunk.”

Congratulations, Dr. Slam Dunk Cronenwett.

This year’s Lifetime Achievement Award winner is called many things by his many nominators: quadruple hitter, visionary, mentor, revolutionary, unsurpassed, profoundly effective. But one thing is mentioned by all.

“Everybody,” they say, “calls him Jack.” That may be because Dr. Jack Cronenwett is not just a legend among SVS members, but he is also unassuming.

“Jack is one of the kindest and most humble person that you could meet,” said Dr. Marc L. Schermerhorn. “I was immediately surprised when I arrived at Dartmouth as a vascular fellow and heard him say, ‘Call me Jack.’ ”

Of Dr. Cronenwett’s – excuse us – Jack’s major achievements, the first was his work at Dartmouth-Hitchcock Medical Center.

In the 1980s, Dartmouth had a relatively small, little-known division of vascular surgery, and Jack was its first vascular surgeon. “He has trained and recruited the entire faculty and turned it into a powerhouse, a division of vascular surgery that has national and international recognition,” wrote Dr. Jens Eldrup-Jorgensen in his nomination.

In addition, Jack was largely responsible for the development at Dartmouth of a new vascular surgery training paradigm – the 0+5 residency. “He had the first program and was instrumental in making this type of program a possibility at the board level,” Dr. Schermerhorn wrote.

Getting a 0+5 program approved by the American Board of Surgery was an almost insurmountable hurdle.

“From my perspective,” said Jack, “it was all about training. We were advocating for a concept. You didn’t need to have full general surgery training in order to become a vascular surgeon. It was inefficient. We needed to be more focused. We couldn’t expand training every time a new procedure came along and still think that these residents needed to know how to do breast surgery.”

“Many of us work in institutions or divisions where we simply had to carry on what had been started by others,” noted Dr. Richard Cambria. “That was not the case at Dartmouth, where the present status of that outstanding vascular surgery division can be traced to Jack Cronenwett.”

The experience of building a program and expanding the processes of a vascular residency program seems to have whetted Jack’s appetite for leadership and educational excellence.

After the millennium, Jack’s legacy mushroomed with these outstanding achievements:

• 2002 – Spearheaded the Vascular Study Group of New England, a regional quality outcomes registry, which became the model for the future Vascular Quality Initiative

• 2003 – Took the reins of SVS as president and, with Dr. Tom Riles, then president of the American Association for Vascular Surgery (AAVS), convinced these organizations to merge and create an independent administrative office in Chicago, creating today’s more inclusive SVS.

• 2003-2008 – Was senior co-editor of the Journal of Vascular Surgery with Dr. James Seeger.

• 2010, 2014 – Was co-editor of the 7th and 8th editions of Rutherford’s Vascular Surgery textbook with Dr. K. Wayne Johnston.

• 2011 – Helped launch the SVS-PSO as an official new entity and has served as medical director since.

The Vascular Study Group of New England: This now well-known quality improvement registry was partially modeled after the Northern New England Cardiovascular Disease Study Group. “It was not just a copycat of NNECVDSG,” noted Dr. Eldrup-Jorgensen. “Biannual regional meetings were developed to promote quality improvement, which is somewhat uncommon for a registry.”

The organization grew and earned the attention of other centers around the country and the world. Under the umbrella of the SVS, the study group opened its membership and renamed itself the Vascular Quality Initiative, which today has 375 centers and a multidisciplinary membership that includes cardiologists and radiologists.

Vascular Quality Initiative: The huge success of the VQI, Dr. Jorgensen added, “required not only wisdom and vision, but also great judgment and the ability to work collaboratively and collegially.”

“Some of us may now take it for granted,” said Dr. Anton Sidawy, “but those of us who were involved in the discussions about VQI remember the endless night calls that we spent listening to Jack making various arguments about why the Society should invest in such a program. He actually had the plan completely conceived, describing the details of the regional concept used currently by VQI. I also remember the many meetings during VAM to discuss the program. Jack had the vision, the persistence and the details to be able to convince the SVS leadership to adopt it. We did, and as they say, the rest is history.”

President of SVS: While serving as SVS president, Jack worked with Dr. Tom Riles to push for the merger of two vascular societies, the SVS and the AAVS, into today’s Society for Vascular Surgery.

Senior co-editor, Journal of Vascular Surgery: As co-editor from 2003-2008, Jack has been recognized for leading significant changes that improved the content, quality and impact of the publication.

“Jack’s tenure on the Journal is when the number of submissions began to accelerate, exceeding a thousand per year,” recalled SVS President Dr. Bruce A. Perler. “He also started a program at the annual meeting to teach reviewers.”

He also served as a senior editor for recent editions of Rutherford’s Vascular Surgery textbook. The modern understanding of the pathophysiology and surgical decision-making surrounding the management of aortoiliac occlusive and infrarenal aortic aneurysm disease is profoundly influenced by his early work. His early studies of actuarial survival after aortic aneurysm surgery and cost effectiveness of asymptomatic carotid endarterectomy have inspired a generation of researchers.

A prolific writer and publisher himself, Jack has published more than 200 peer-reviewed journal articles, contributed chapters to more than 50 books, co-edited 14 books, delivered more than 300 invited presentations, and made nearly 200 peer-reviewed presentations at regional and national meetings.

In response to receiving this award, Jack expressed profound gratitude to his colleagues in the SVS for this recognition. “To me, this should really be called the SVS Lifetime ‘Opportunity’ Award. I have been afforded so many opportunities by the SVS during my life, which are only exceeded by the great number of close friendships that I have developed through the SVS. This has been a privilege and source of great gratification for me throughout my career.”

Among all his nominators and their excellent, thorough and effusive recommendations, Dr. Larry Kraiss summed it up as well as anyone: “Jack’s contributions outside of the VQI would make him a very strong candidate for the Lifetime Achievement Award. When you credit him with the VQI and its long-term positive impact on the SVS, I think he is a slam dunk.”

Congratulations, Dr. Slam Dunk Cronenwett.

This year’s Lifetime Achievement Award winner is called many things by his many nominators: quadruple hitter, visionary, mentor, revolutionary, unsurpassed, profoundly effective. But one thing is mentioned by all.

“Everybody,” they say, “calls him Jack.” That may be because Dr. Jack Cronenwett is not just a legend among SVS members, but he is also unassuming.

“Jack is one of the kindest and most humble person that you could meet,” said Dr. Marc L. Schermerhorn. “I was immediately surprised when I arrived at Dartmouth as a vascular fellow and heard him say, ‘Call me Jack.’ ”

Of Dr. Cronenwett’s – excuse us – Jack’s major achievements, the first was his work at Dartmouth-Hitchcock Medical Center.

In the 1980s, Dartmouth had a relatively small, little-known division of vascular surgery, and Jack was its first vascular surgeon. “He has trained and recruited the entire faculty and turned it into a powerhouse, a division of vascular surgery that has national and international recognition,” wrote Dr. Jens Eldrup-Jorgensen in his nomination.

In addition, Jack was largely responsible for the development at Dartmouth of a new vascular surgery training paradigm – the 0+5 residency. “He had the first program and was instrumental in making this type of program a possibility at the board level,” Dr. Schermerhorn wrote.

Getting a 0+5 program approved by the American Board of Surgery was an almost insurmountable hurdle.

“From my perspective,” said Jack, “it was all about training. We were advocating for a concept. You didn’t need to have full general surgery training in order to become a vascular surgeon. It was inefficient. We needed to be more focused. We couldn’t expand training every time a new procedure came along and still think that these residents needed to know how to do breast surgery.”

“Many of us work in institutions or divisions where we simply had to carry on what had been started by others,” noted Dr. Richard Cambria. “That was not the case at Dartmouth, where the present status of that outstanding vascular surgery division can be traced to Jack Cronenwett.”

The experience of building a program and expanding the processes of a vascular residency program seems to have whetted Jack’s appetite for leadership and educational excellence.

After the millennium, Jack’s legacy mushroomed with these outstanding achievements:

• 2002 – Spearheaded the Vascular Study Group of New England, a regional quality outcomes registry, which became the model for the future Vascular Quality Initiative

• 2003 – Took the reins of SVS as president and, with Dr. Tom Riles, then president of the American Association for Vascular Surgery (AAVS), convinced these organizations to merge and create an independent administrative office in Chicago, creating today’s more inclusive SVS.

• 2003-2008 – Was senior co-editor of the Journal of Vascular Surgery with Dr. James Seeger.

• 2010, 2014 – Was co-editor of the 7th and 8th editions of Rutherford’s Vascular Surgery textbook with Dr. K. Wayne Johnston.

• 2011 – Helped launch the SVS-PSO as an official new entity and has served as medical director since.

The Vascular Study Group of New England: This now well-known quality improvement registry was partially modeled after the Northern New England Cardiovascular Disease Study Group. “It was not just a copycat of NNECVDSG,” noted Dr. Eldrup-Jorgensen. “Biannual regional meetings were developed to promote quality improvement, which is somewhat uncommon for a registry.”

The organization grew and earned the attention of other centers around the country and the world. Under the umbrella of the SVS, the study group opened its membership and renamed itself the Vascular Quality Initiative, which today has 375 centers and a multidisciplinary membership that includes cardiologists and radiologists.

Vascular Quality Initiative: The huge success of the VQI, Dr. Jorgensen added, “required not only wisdom and vision, but also great judgment and the ability to work collaboratively and collegially.”

“Some of us may now take it for granted,” said Dr. Anton Sidawy, “but those of us who were involved in the discussions about VQI remember the endless night calls that we spent listening to Jack making various arguments about why the Society should invest in such a program. He actually had the plan completely conceived, describing the details of the regional concept used currently by VQI. I also remember the many meetings during VAM to discuss the program. Jack had the vision, the persistence and the details to be able to convince the SVS leadership to adopt it. We did, and as they say, the rest is history.”

President of SVS: While serving as SVS president, Jack worked with Dr. Tom Riles to push for the merger of two vascular societies, the SVS and the AAVS, into today’s Society for Vascular Surgery.

Senior co-editor, Journal of Vascular Surgery: As co-editor from 2003-2008, Jack has been recognized for leading significant changes that improved the content, quality and impact of the publication.

“Jack’s tenure on the Journal is when the number of submissions began to accelerate, exceeding a thousand per year,” recalled SVS President Dr. Bruce A. Perler. “He also started a program at the annual meeting to teach reviewers.”

He also served as a senior editor for recent editions of Rutherford’s Vascular Surgery textbook. The modern understanding of the pathophysiology and surgical decision-making surrounding the management of aortoiliac occlusive and infrarenal aortic aneurysm disease is profoundly influenced by his early work. His early studies of actuarial survival after aortic aneurysm surgery and cost effectiveness of asymptomatic carotid endarterectomy have inspired a generation of researchers.

A prolific writer and publisher himself, Jack has published more than 200 peer-reviewed journal articles, contributed chapters to more than 50 books, co-edited 14 books, delivered more than 300 invited presentations, and made nearly 200 peer-reviewed presentations at regional and national meetings.

In response to receiving this award, Jack expressed profound gratitude to his colleagues in the SVS for this recognition. “To me, this should really be called the SVS Lifetime ‘Opportunity’ Award. I have been afforded so many opportunities by the SVS during my life, which are only exceeded by the great number of close friendships that I have developed through the SVS. This has been a privilege and source of great gratification for me throughout my career.”

Among all his nominators and their excellent, thorough and effusive recommendations, Dr. Larry Kraiss summed it up as well as anyone: “Jack’s contributions outside of the VQI would make him a very strong candidate for the Lifetime Achievement Award. When you credit him with the VQI and its long-term positive impact on the SVS, I think he is a slam dunk.”

Congratulations, Dr. Slam Dunk Cronenwett.

NATIONAL HARBOR, MD. – Follow-up of a cohort of patients in the United Kingdom has demonstrated associations between smoking and a higher risk of development of multiple sclerosis (MS), progression of MS-related disability, higher risk of premature death, and shortened life expectancy.

The findings highlight the need for clinical trials of the effects of quitting smoking and provide data that will be useful in the development of effective intervention strategies.

Dr. Cris S. Constantinescu of the University of Nottingham (England) discussed findings from the Nottingham University Hospitals MS Clinics database at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Although smokers had higher levels of comorbid conditions, it appeared that the influence of smoking is independent of the presence of comorbid conditions. Those who gave up smoking could do as well as nonsmokers,” said Dr. Constantinescu.

While ample epidemiologic evidence indicates that smoking is a driver of the development and progression of MS, there are few hard data. To gain insight, the researchers analyzed data on over 1,200 MS patients throughout England who were followed up beginning in the mid-1990s. About 60% of the patients had relapsing-remitting MS. The duration of MS and smoking were both about 20 years. About 60% of men and 50% of women were current smokers.

Regular smokers were 64% more likely to develop MS than were nonsmokers. Having ever smoked carried a 44% increased risk of MS (both P less than .001). MS patients who grew up in a household where one parent smoked were 50% more likely to become regular smokers. The risk climbed to 85% if both parents were smokers.

No association was evident between smoking and the development of primary progressive MS, but current smokers were almost 2.5 times more likely to develop secondary progressive MS. Smoking correlated with more severe MS disability, compared with nonsmokers. Ex-smokers had risks similar to those of nonsmokers of developing secondary MS and in the level of disease severity.

Every year a person refrained from smoking decreased the risk of severe disability by 5%. Current and ex-smokers displayed increased psychological and physical detriments of MS.

In a subgroup of 923 patients, of whom 80 died, current smokers were almost 3 times and 1.5 times more likely to die, compared with never smokers and ex-smokers, respectively, and were twice as likely to die as were people without MS in the UK general population.

The findings have prompted studies into major aspects of smoking, such as the age when smoking begins, the success of various smoking cessation programs, and development of interventions. Some of the data discussed at the meeting were published in 2013 (Brain;136:2298-2304) and some are part of a manuscript in preparation.

NATIONAL HARBOR, MD. – Follow-up of a cohort of patients in the United Kingdom has demonstrated associations between smoking and a higher risk of development of multiple sclerosis (MS), progression of MS-related disability, higher risk of premature death, and shortened life expectancy.

The findings highlight the need for clinical trials of the effects of quitting smoking and provide data that will be useful in the development of effective intervention strategies.

Dr. Cris S. Constantinescu of the University of Nottingham (England) discussed findings from the Nottingham University Hospitals MS Clinics database at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Although smokers had higher levels of comorbid conditions, it appeared that the influence of smoking is independent of the presence of comorbid conditions. Those who gave up smoking could do as well as nonsmokers,” said Dr. Constantinescu.

While ample epidemiologic evidence indicates that smoking is a driver of the development and progression of MS, there are few hard data. To gain insight, the researchers analyzed data on over 1,200 MS patients throughout England who were followed up beginning in the mid-1990s. About 60% of the patients had relapsing-remitting MS. The duration of MS and smoking were both about 20 years. About 60% of men and 50% of women were current smokers.

Regular smokers were 64% more likely to develop MS than were nonsmokers. Having ever smoked carried a 44% increased risk of MS (both P less than .001). MS patients who grew up in a household where one parent smoked were 50% more likely to become regular smokers. The risk climbed to 85% if both parents were smokers.

No association was evident between smoking and the development of primary progressive MS, but current smokers were almost 2.5 times more likely to develop secondary progressive MS. Smoking correlated with more severe MS disability, compared with nonsmokers. Ex-smokers had risks similar to those of nonsmokers of developing secondary MS and in the level of disease severity.

Every year a person refrained from smoking decreased the risk of severe disability by 5%. Current and ex-smokers displayed increased psychological and physical detriments of MS.

In a subgroup of 923 patients, of whom 80 died, current smokers were almost 3 times and 1.5 times more likely to die, compared with never smokers and ex-smokers, respectively, and were twice as likely to die as were people without MS in the UK general population.

The findings have prompted studies into major aspects of smoking, such as the age when smoking begins, the success of various smoking cessation programs, and development of interventions. Some of the data discussed at the meeting were published in 2013 (Brain;136:2298-2304) and some are part of a manuscript in preparation.

NATIONAL HARBOR, MD. – Follow-up of a cohort of patients in the United Kingdom has demonstrated associations between smoking and a higher risk of development of multiple sclerosis (MS), progression of MS-related disability, higher risk of premature death, and shortened life expectancy.

The findings highlight the need for clinical trials of the effects of quitting smoking and provide data that will be useful in the development of effective intervention strategies.

Dr. Cris S. Constantinescu of the University of Nottingham (England) discussed findings from the Nottingham University Hospitals MS Clinics database at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Although smokers had higher levels of comorbid conditions, it appeared that the influence of smoking is independent of the presence of comorbid conditions. Those who gave up smoking could do as well as nonsmokers,” said Dr. Constantinescu.

While ample epidemiologic evidence indicates that smoking is a driver of the development and progression of MS, there are few hard data. To gain insight, the researchers analyzed data on over 1,200 MS patients throughout England who were followed up beginning in the mid-1990s. About 60% of the patients had relapsing-remitting MS. The duration of MS and smoking were both about 20 years. About 60% of men and 50% of women were current smokers.

Regular smokers were 64% more likely to develop MS than were nonsmokers. Having ever smoked carried a 44% increased risk of MS (both P less than .001). MS patients who grew up in a household where one parent smoked were 50% more likely to become regular smokers. The risk climbed to 85% if both parents were smokers.

No association was evident between smoking and the development of primary progressive MS, but current smokers were almost 2.5 times more likely to develop secondary progressive MS. Smoking correlated with more severe MS disability, compared with nonsmokers. Ex-smokers had risks similar to those of nonsmokers of developing secondary MS and in the level of disease severity.

Every year a person refrained from smoking decreased the risk of severe disability by 5%. Current and ex-smokers displayed increased psychological and physical detriments of MS.

In a subgroup of 923 patients, of whom 80 died, current smokers were almost 3 times and 1.5 times more likely to die, compared with never smokers and ex-smokers, respectively, and were twice as likely to die as were people without MS in the UK general population.

The findings have prompted studies into major aspects of smoking, such as the age when smoking begins, the success of various smoking cessation programs, and development of interventions. Some of the data discussed at the meeting were published in 2013 (Brain;136:2298-2304) and some are part of a manuscript in preparation.

CHICAGO – More children treated for high-risk neuroblastoma who received a second autologous stem cell transplant in consolidation after induction chemotherapy were alive after 3 years compared with children getting a single transplant, Dr. Julie R. Park reported at the annual meeting of the American Society of Clinical Oncology.

Neuroblastoma (NB) is the most common extracranial tumor of childhood and arises in the sympathetic nervous system of very young children. Fewer than 50% of children with high-risk NB survive 5 years following today’s multiagent, aggressive therapy. Single autologous hematopoietic stem cell transplant (ASCT) has improved outcomes, and in pilot studies, tandem ASCT appeared tolerable with better efficacy as consolidation therapy for high-risk NB.

The present trial enrolled 665 patients (mean age 3.1 years), who received an induction regimen of six cycles of chemotherapy, with harvest of peripheral blood stem cells after the first two cycles and surgery after five cycles. Patients with adequate stem cell collection, adequate organ function, and no evidence of disease progression were randomized to either standard therapy with a single ASCT with carboplatin, etoposide, melphalan and local radiotherapy (n = 179); or to a double (tandem) ASCT with cyclophosphamide and thiotepa prior to the first ASCT followed 6 weeks later by a dose-modified regimen of carboplatin, etoposide, melphalan and radiotherapy prior to a second ASCT (n = 176). The two transplants were separated by 6-8 weeks.

About 70% of patients in each arm received dinutuximab plus cytokine immunotherapy after their transplants. Dinutuximab is an antibody directed against GD2, an antigen present on neuroblastoma cells. About 38% of patients had high-risk tumors based on the presence of MYCN gene amplification.

The children who were randomized to receive a tandem transplant had a statistically significant, improved event-free survival, with a 3-year event-free survival of 61%, compared to those children receiving a single transplant, with a 3-year event-free survival of 48% (P = .0081), reported Dr. Park, professor of pediatrics at the University of Washington, Seattle.

Three-year overall survival did not differ between the two groups, at 74% for the tandem transplant group and 69% for the single transplant group (P = .185). The study was powered to see a difference in event-free survival, and the study was probably not long enough to detect a difference in overall survival, Dr. Park said.

Anti-GD2 immunotherapy improved both event-free and overall survival for both the tandem and single ASCT groups. At 3 years from the time of the patients’ receiving immunotherapy, event-free survival was 73.7% and 56%, respectively (P = .0033), and overall survival was 83.7% and 74.4% (P = .0322), respectively.

The benefit of tandem transplant occurred without an increase in toxicity or regimen-related mortality. The rates of severe toxicities were similar in the two arms. Two patients receiving a tandem ASCT died, compared with eight receiving a single ASCT.

“This finding will change the way we treat children with high-risk neuroblastoma in North America, which still claims many young lives and is in urgent need of better treatments,” Dr. Park said in a press release.

Dr. Park noted that most NB recurrences happen within 2-3 years from diagnosis and that patients who have not had a recurrence by 3 years have a better chance of long-term survival. Patients in this study will continue to be followed for 10 years.

Dr. Park disclosed ties with Roche. Dr. Hunger reported ties with Merck, Sigma Tau, Jazz Pharmaceuticals, and Spectrum Pharmaceuticals.

CHICAGO – More children treated for high-risk neuroblastoma who received a second autologous stem cell transplant in consolidation after induction chemotherapy were alive after 3 years compared with children getting a single transplant, Dr. Julie R. Park reported at the annual meeting of the American Society of Clinical Oncology.

Neuroblastoma (NB) is the most common extracranial tumor of childhood and arises in the sympathetic nervous system of very young children. Fewer than 50% of children with high-risk NB survive 5 years following today’s multiagent, aggressive therapy. Single autologous hematopoietic stem cell transplant (ASCT) has improved outcomes, and in pilot studies, tandem ASCT appeared tolerable with better efficacy as consolidation therapy for high-risk NB.

The present trial enrolled 665 patients (mean age 3.1 years), who received an induction regimen of six cycles of chemotherapy, with harvest of peripheral blood stem cells after the first two cycles and surgery after five cycles. Patients with adequate stem cell collection, adequate organ function, and no evidence of disease progression were randomized to either standard therapy with a single ASCT with carboplatin, etoposide, melphalan and local radiotherapy (n = 179); or to a double (tandem) ASCT with cyclophosphamide and thiotepa prior to the first ASCT followed 6 weeks later by a dose-modified regimen of carboplatin, etoposide, melphalan and radiotherapy prior to a second ASCT (n = 176). The two transplants were separated by 6-8 weeks.

About 70% of patients in each arm received dinutuximab plus cytokine immunotherapy after their transplants. Dinutuximab is an antibody directed against GD2, an antigen present on neuroblastoma cells. About 38% of patients had high-risk tumors based on the presence of MYCN gene amplification.

The children who were randomized to receive a tandem transplant had a statistically significant, improved event-free survival, with a 3-year event-free survival of 61%, compared to those children receiving a single transplant, with a 3-year event-free survival of 48% (P = .0081), reported Dr. Park, professor of pediatrics at the University of Washington, Seattle.

Three-year overall survival did not differ between the two groups, at 74% for the tandem transplant group and 69% for the single transplant group (P = .185). The study was powered to see a difference in event-free survival, and the study was probably not long enough to detect a difference in overall survival, Dr. Park said.

Anti-GD2 immunotherapy improved both event-free and overall survival for both the tandem and single ASCT groups. At 3 years from the time of the patients’ receiving immunotherapy, event-free survival was 73.7% and 56%, respectively (P = .0033), and overall survival was 83.7% and 74.4% (P = .0322), respectively.

The benefit of tandem transplant occurred without an increase in toxicity or regimen-related mortality. The rates of severe toxicities were similar in the two arms. Two patients receiving a tandem ASCT died, compared with eight receiving a single ASCT.

“This finding will change the way we treat children with high-risk neuroblastoma in North America, which still claims many young lives and is in urgent need of better treatments,” Dr. Park said in a press release.

Dr. Park noted that most NB recurrences happen within 2-3 years from diagnosis and that patients who have not had a recurrence by 3 years have a better chance of long-term survival. Patients in this study will continue to be followed for 10 years.

Dr. Park disclosed ties with Roche. Dr. Hunger reported ties with Merck, Sigma Tau, Jazz Pharmaceuticals, and Spectrum Pharmaceuticals.

CHICAGO – More children treated for high-risk neuroblastoma who received a second autologous stem cell transplant in consolidation after induction chemotherapy were alive after 3 years compared with children getting a single transplant, Dr. Julie R. Park reported at the annual meeting of the American Society of Clinical Oncology.

Neuroblastoma (NB) is the most common extracranial tumor of childhood and arises in the sympathetic nervous system of very young children. Fewer than 50% of children with high-risk NB survive 5 years following today’s multiagent, aggressive therapy. Single autologous hematopoietic stem cell transplant (ASCT) has improved outcomes, and in pilot studies, tandem ASCT appeared tolerable with better efficacy as consolidation therapy for high-risk NB.

The present trial enrolled 665 patients (mean age 3.1 years), who received an induction regimen of six cycles of chemotherapy, with harvest of peripheral blood stem cells after the first two cycles and surgery after five cycles. Patients with adequate stem cell collection, adequate organ function, and no evidence of disease progression were randomized to either standard therapy with a single ASCT with carboplatin, etoposide, melphalan and local radiotherapy (n = 179); or to a double (tandem) ASCT with cyclophosphamide and thiotepa prior to the first ASCT followed 6 weeks later by a dose-modified regimen of carboplatin, etoposide, melphalan and radiotherapy prior to a second ASCT (n = 176). The two transplants were separated by 6-8 weeks.

About 70% of patients in each arm received dinutuximab plus cytokine immunotherapy after their transplants. Dinutuximab is an antibody directed against GD2, an antigen present on neuroblastoma cells. About 38% of patients had high-risk tumors based on the presence of MYCN gene amplification.

The children who were randomized to receive a tandem transplant had a statistically significant, improved event-free survival, with a 3-year event-free survival of 61%, compared to those children receiving a single transplant, with a 3-year event-free survival of 48% (P = .0081), reported Dr. Park, professor of pediatrics at the University of Washington, Seattle.

Three-year overall survival did not differ between the two groups, at 74% for the tandem transplant group and 69% for the single transplant group (P = .185). The study was powered to see a difference in event-free survival, and the study was probably not long enough to detect a difference in overall survival, Dr. Park said.

Anti-GD2 immunotherapy improved both event-free and overall survival for both the tandem and single ASCT groups. At 3 years from the time of the patients’ receiving immunotherapy, event-free survival was 73.7% and 56%, respectively (P = .0033), and overall survival was 83.7% and 74.4% (P = .0322), respectively.

The benefit of tandem transplant occurred without an increase in toxicity or regimen-related mortality. The rates of severe toxicities were similar in the two arms. Two patients receiving a tandem ASCT died, compared with eight receiving a single ASCT.

“This finding will change the way we treat children with high-risk neuroblastoma in North America, which still claims many young lives and is in urgent need of better treatments,” Dr. Park said in a press release.

Dr. Park noted that most NB recurrences happen within 2-3 years from diagnosis and that patients who have not had a recurrence by 3 years have a better chance of long-term survival. Patients in this study will continue to be followed for 10 years.

Dr. Park disclosed ties with Roche. Dr. Hunger reported ties with Merck, Sigma Tau, Jazz Pharmaceuticals, and Spectrum Pharmaceuticals.

As a resident in psychiatry, I am being trained in the art of diagnosis, treatment, and prevention of mental illness and emotional problems. As part of my training, research and scholarly activities are encouraged—reminding us that clinical medicine is always evolving and that it is every physician’s duty to be at the forefront of advancements in medical science.

Last year, I worked in the clinical trial industry under a seasoned principal investigator. I learned several lessons from my time with him and in the industry. Here, I present these lessons as a starting point for residents who are looking to gain experience or contemplating a career as an expert trialist or principal investigator.

Lesson 1: Know the lingo
To make the transition from physician to principal investigator go more smoothly, I recommend taking the time to learn the language of the industry. The good news? Clinical trials involve patients who have a medical history and take medications, which you are well acquainted with. In addition to medical jargon, the industry has developed its own distinctive terminology and abbreviations: adverse drug reaction (ADR), good clinical practice (GCP), contract research organization (CRO), and more.

Don’t stop there, however. I recommend that you read FDA research guidelines and guidelines of the International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) to be familiar with the ethics and standard regulations of the industry.

Lesson 2: When in doubt, refer to the Protocol
Every clinical trial has a manual, so to speak, known as the Study Protocol, which outlines approved methods of performing diagnostic tests and procedures; provides information on the study timeline; and specifies patient inclusion and exclusion criteria. This document ensures conformity across all study sites, helps prevent errors, limits bias, and answers questions that might come up during the study. It’s worth noting that, in my experience, many of the questions about exclusionary medications arise when psychiatric drugs are involved.

Lesson 3: Document. Document. And document.
The golden rule in clinical practice and research is: “If it isn’t documented, it didn’t happen.” (Recall what I said about reading FDA and ICH-GCP guidelines to learn about regulations.) Documentation of all study-related activities must be meticulous. At any time, your documents might be subject to external or internal audit, conducted to preserve conformity to the protocol and maintain patient safety. Improper documentation can delay, even invalidate, your research.

Lesson 4: Remember that advertising is an art
The real work begins when your site is ready to accept patients. To fill the study, patients need to be aware that you are recruiting participants. A good starting point is to inform likely candidates from your existing patient population about any studies from which they might benefit.

Most times, however, recruiting among your patients is not enough to meet necessary enrollment numbers. You will have to advertise the study to the general public. Advertisements must target the specific patient population, informing them of the study but, at the same time, not be coercive or make false promises. The advertisements must be approved by the study’s institutional review board, which is responsible for protecting the rights and welfare of study participants.

Advertising can be tricky. If an advertisement is too vague, you will get a huge response, causing time and resources to be spent screening patients—most of whom might not be suitable for the study. If an advertisement is too specific, on the other hand, the response might be poor or none at all.

Advertising is its own industry. It might be best to hire an advertising expert who can help you decide on the selection of media (radio, television, print, digital) and can design a campaign that best suits your needs. If you decide to hire a professional, I recommend close collaboration with him (her), to help him understand the medical nature of the study.

Related Resources

• ClinicalTrials.gov. About clinical studies. https://clinicaltrials.gov/ct2/about-studies.

• U.S. Food and Drug Administration. Clinical trials and human subject protection. http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.

• ICH GCP. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use. http://ichgcp.net/.

As a resident in psychiatry, I am being trained in the art of diagnosis, treatment, and prevention of mental illness and emotional problems. As part of my training, research and scholarly activities are encouraged—reminding us that clinical medicine is always evolving and that it is every physician’s duty to be at the forefront of advancements in medical science.

Last year, I worked in the clinical trial industry under a seasoned principal investigator. I learned several lessons from my time with him and in the industry. Here, I present these lessons as a starting point for residents who are looking to gain experience or contemplating a career as an expert trialist or principal investigator.

Lesson 1: Know the lingo
To make the transition from physician to principal investigator go more smoothly, I recommend taking the time to learn the language of the industry. The good news? Clinical trials involve patients who have a medical history and take medications, which you are well acquainted with. In addition to medical jargon, the industry has developed its own distinctive terminology and abbreviations: adverse drug reaction (ADR), good clinical practice (GCP), contract research organization (CRO), and more.

Don’t stop there, however. I recommend that you read FDA research guidelines and guidelines of the International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) to be familiar with the ethics and standard regulations of the industry.

Lesson 2: When in doubt, refer to the Protocol
Every clinical trial has a manual, so to speak, known as the Study Protocol, which outlines approved methods of performing diagnostic tests and procedures; provides information on the study timeline; and specifies patient inclusion and exclusion criteria. This document ensures conformity across all study sites, helps prevent errors, limits bias, and answers questions that might come up during the study. It’s worth noting that, in my experience, many of the questions about exclusionary medications arise when psychiatric drugs are involved.

Lesson 3: Document. Document. And document.
The golden rule in clinical practice and research is: “If it isn’t documented, it didn’t happen.” (Recall what I said about reading FDA and ICH-GCP guidelines to learn about regulations.) Documentation of all study-related activities must be meticulous. At any time, your documents might be subject to external or internal audit, conducted to preserve conformity to the protocol and maintain patient safety. Improper documentation can delay, even invalidate, your research.

Lesson 4: Remember that advertising is an art
The real work begins when your site is ready to accept patients. To fill the study, patients need to be aware that you are recruiting participants. A good starting point is to inform likely candidates from your existing patient population about any studies from which they might benefit.

Most times, however, recruiting among your patients is not enough to meet necessary enrollment numbers. You will have to advertise the study to the general public. Advertisements must target the specific patient population, informing them of the study but, at the same time, not be coercive or make false promises. The advertisements must be approved by the study’s institutional review board, which is responsible for protecting the rights and welfare of study participants.

Advertising can be tricky. If an advertisement is too vague, you will get a huge response, causing time and resources to be spent screening patients—most of whom might not be suitable for the study. If an advertisement is too specific, on the other hand, the response might be poor or none at all.

Advertising is its own industry. It might be best to hire an advertising expert who can help you decide on the selection of media (radio, television, print, digital) and can design a campaign that best suits your needs. If you decide to hire a professional, I recommend close collaboration with him (her), to help him understand the medical nature of the study.

Related Resources

• ClinicalTrials.gov. About clinical studies. https://clinicaltrials.gov/ct2/about-studies.

• U.S. Food and Drug Administration. Clinical trials and human subject protection. http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.

• ICH GCP. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use. http://ichgcp.net/.

As a resident in psychiatry, I am being trained in the art of diagnosis, treatment, and prevention of mental illness and emotional problems. As part of my training, research and scholarly activities are encouraged—reminding us that clinical medicine is always evolving and that it is every physician’s duty to be at the forefront of advancements in medical science.

Last year, I worked in the clinical trial industry under a seasoned principal investigator. I learned several lessons from my time with him and in the industry. Here, I present these lessons as a starting point for residents who are looking to gain experience or contemplating a career as an expert trialist or principal investigator.

Lesson 1: Know the lingo
To make the transition from physician to principal investigator go more smoothly, I recommend taking the time to learn the language of the industry. The good news? Clinical trials involve patients who have a medical history and take medications, which you are well acquainted with. In addition to medical jargon, the industry has developed its own distinctive terminology and abbreviations: adverse drug reaction (ADR), good clinical practice (GCP), contract research organization (CRO), and more.

Don’t stop there, however. I recommend that you read FDA research guidelines and guidelines of the International Conference on Harmonisation of Good Clinical Practice (ICH-GCP) to be familiar with the ethics and standard regulations of the industry.

Lesson 2: When in doubt, refer to the Protocol
Every clinical trial has a manual, so to speak, known as the Study Protocol, which outlines approved methods of performing diagnostic tests and procedures; provides information on the study timeline; and specifies patient inclusion and exclusion criteria. This document ensures conformity across all study sites, helps prevent errors, limits bias, and answers questions that might come up during the study. It’s worth noting that, in my experience, many of the questions about exclusionary medications arise when psychiatric drugs are involved.

Lesson 3: Document. Document. And document.
The golden rule in clinical practice and research is: “If it isn’t documented, it didn’t happen.” (Recall what I said about reading FDA and ICH-GCP guidelines to learn about regulations.) Documentation of all study-related activities must be meticulous. At any time, your documents might be subject to external or internal audit, conducted to preserve conformity to the protocol and maintain patient safety. Improper documentation can delay, even invalidate, your research.

Lesson 4: Remember that advertising is an art
The real work begins when your site is ready to accept patients. To fill the study, patients need to be aware that you are recruiting participants. A good starting point is to inform likely candidates from your existing patient population about any studies from which they might benefit.

Most times, however, recruiting among your patients is not enough to meet necessary enrollment numbers. You will have to advertise the study to the general public. Advertisements must target the specific patient population, informing them of the study but, at the same time, not be coercive or make false promises. The advertisements must be approved by the study’s institutional review board, which is responsible for protecting the rights and welfare of study participants.

Advertising can be tricky. If an advertisement is too vague, you will get a huge response, causing time and resources to be spent screening patients—most of whom might not be suitable for the study. If an advertisement is too specific, on the other hand, the response might be poor or none at all.

Advertising is its own industry. It might be best to hire an advertising expert who can help you decide on the selection of media (radio, television, print, digital) and can design a campaign that best suits your needs. If you decide to hire a professional, I recommend close collaboration with him (her), to help him understand the medical nature of the study.

Related Resources

• ClinicalTrials.gov. About clinical studies. https://clinicaltrials.gov/ct2/about-studies.

• U.S. Food and Drug Administration. Clinical trials and human subject protection. http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.

• ICH GCP. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use. http://ichgcp.net/.