Read the digital edition here.

Read the digital edition here.

Read the digital edition here.

Patients with chronic obstructive pulmonary disease with shorter telomere lengths in their peripheral white blood cells may be at greater risk of exacerbations and death, according to a study published in Chest.

U.S. Department of Energy

The evidence suggests that chronic obstructive pulmonary disease (COPD) may be a disease of accelerated aging, partly because of its relation to other senescence-related disorders such as osteoporosis and dementia, but also because it shows an exponential increase in prevalence in older age.

Telomere lengths are a measure of cellular senescence, and previous research has found that the telomeres are shortened in the peripheral leukocytes of patients with COPD, compared with healthy controls.

In this study, researchers examined the absolute telomere length of 576 people with moderate to severe COPD who were participating in the MACRO (Macrolide Azithromycin for Prevention of Exacerbations of COPD) study.

They found that individuals in the lowest quartile of telomere lengths had significantly worse health status and a higher exacerbation rate after accounting for treatment, compared with individuals in the higher quartile.

Patients with shorter telomere length had worse health status, as defined by higher St. George’s Respiratory Questionnaire scores. In the placebo arm of the study, the exacerbation rate (rate ratio, 1.50; 95% confidence interval, 1.16-1.95; P = .002) and mortality risk (hazard ratio, 9.45; 95% CI, 2.85-31.36; P = .015) were significantly higher in the shorter telomere group than in the longer telomere group; these differences were not observed in the azithromycin arm.

Patients with shorter telomeres also had a 800% higher risk of total mortality, compared with individuals with longer telomeres, although this was only evident in the placebo arm of the study, not the azithromycin arm. However, the authors noted that these data should be interpreted with caution because of the small number of deaths during the study.

“Together, these data support the notion that COPD is a systemic disease of accelerated aging and that replicative senescence, denoted by peripheral blood telomeres, is associated with poor health outcomes in COPD,” wrote Minhee Jin, of the University of British Columbia, Vancouver, and coauthors.

“It is now well established that replicative senescence results in a change of cellular phenotype to a proinflammatory state, a process that has been referred to as senescence-associated secretory phenotype,” they added.

The study also found that the median value for telomere length across the study participants – who had a mean age of 66 years – was equivalent to the expected value for someone in their 80s, “suggesting that on average MACRO participants were biologically much older than their chronological age.”

Researchers also noted that patients in the lowest quartile of telomere length had significantly lower forced vital capacity values, which suggested shorter telomeres could be a biomarker of restrictive physiology.

MACRO was funded by the U.S. National Heart, Lung, and Blood Institute, and the biomarker component of the study was funded by the Canadian Respiratory Research Network, Genome Canada, and the St. Paul’s Hospital Foundation. One author was an employee of GenomeDx Biosciences, three declared funding from or consultancies with the pharmaceutical industry. No other conflicts of interest were reported.

SOURCE: Jin M et al. Chest. 2018 Jul 12. doi: 10.1016/j.chest.2018.05.022.

Patients with chronic obstructive pulmonary disease with shorter telomere lengths in their peripheral white blood cells may be at greater risk of exacerbations and death, according to a study published in Chest.

U.S. Department of Energy

The evidence suggests that chronic obstructive pulmonary disease (COPD) may be a disease of accelerated aging, partly because of its relation to other senescence-related disorders such as osteoporosis and dementia, but also because it shows an exponential increase in prevalence in older age.

Telomere lengths are a measure of cellular senescence, and previous research has found that the telomeres are shortened in the peripheral leukocytes of patients with COPD, compared with healthy controls.

In this study, researchers examined the absolute telomere length of 576 people with moderate to severe COPD who were participating in the MACRO (Macrolide Azithromycin for Prevention of Exacerbations of COPD) study.

They found that individuals in the lowest quartile of telomere lengths had significantly worse health status and a higher exacerbation rate after accounting for treatment, compared with individuals in the higher quartile.

Patients with shorter telomere length had worse health status, as defined by higher St. George’s Respiratory Questionnaire scores. In the placebo arm of the study, the exacerbation rate (rate ratio, 1.50; 95% confidence interval, 1.16-1.95; P = .002) and mortality risk (hazard ratio, 9.45; 95% CI, 2.85-31.36; P = .015) were significantly higher in the shorter telomere group than in the longer telomere group; these differences were not observed in the azithromycin arm.

Patients with shorter telomeres also had a 800% higher risk of total mortality, compared with individuals with longer telomeres, although this was only evident in the placebo arm of the study, not the azithromycin arm. However, the authors noted that these data should be interpreted with caution because of the small number of deaths during the study.

“Together, these data support the notion that COPD is a systemic disease of accelerated aging and that replicative senescence, denoted by peripheral blood telomeres, is associated with poor health outcomes in COPD,” wrote Minhee Jin, of the University of British Columbia, Vancouver, and coauthors.

“It is now well established that replicative senescence results in a change of cellular phenotype to a proinflammatory state, a process that has been referred to as senescence-associated secretory phenotype,” they added.

The study also found that the median value for telomere length across the study participants – who had a mean age of 66 years – was equivalent to the expected value for someone in their 80s, “suggesting that on average MACRO participants were biologically much older than their chronological age.”

Researchers also noted that patients in the lowest quartile of telomere length had significantly lower forced vital capacity values, which suggested shorter telomeres could be a biomarker of restrictive physiology.

MACRO was funded by the U.S. National Heart, Lung, and Blood Institute, and the biomarker component of the study was funded by the Canadian Respiratory Research Network, Genome Canada, and the St. Paul’s Hospital Foundation. One author was an employee of GenomeDx Biosciences, three declared funding from or consultancies with the pharmaceutical industry. No other conflicts of interest were reported.

SOURCE: Jin M et al. Chest. 2018 Jul 12. doi: 10.1016/j.chest.2018.05.022.

Patients with chronic obstructive pulmonary disease with shorter telomere lengths in their peripheral white blood cells may be at greater risk of exacerbations and death, according to a study published in Chest.

U.S. Department of Energy

The evidence suggests that chronic obstructive pulmonary disease (COPD) may be a disease of accelerated aging, partly because of its relation to other senescence-related disorders such as osteoporosis and dementia, but also because it shows an exponential increase in prevalence in older age.

Telomere lengths are a measure of cellular senescence, and previous research has found that the telomeres are shortened in the peripheral leukocytes of patients with COPD, compared with healthy controls.

In this study, researchers examined the absolute telomere length of 576 people with moderate to severe COPD who were participating in the MACRO (Macrolide Azithromycin for Prevention of Exacerbations of COPD) study.

They found that individuals in the lowest quartile of telomere lengths had significantly worse health status and a higher exacerbation rate after accounting for treatment, compared with individuals in the higher quartile.

Patients with shorter telomere length had worse health status, as defined by higher St. George’s Respiratory Questionnaire scores. In the placebo arm of the study, the exacerbation rate (rate ratio, 1.50; 95% confidence interval, 1.16-1.95; P = .002) and mortality risk (hazard ratio, 9.45; 95% CI, 2.85-31.36; P = .015) were significantly higher in the shorter telomere group than in the longer telomere group; these differences were not observed in the azithromycin arm.

Patients with shorter telomeres also had a 800% higher risk of total mortality, compared with individuals with longer telomeres, although this was only evident in the placebo arm of the study, not the azithromycin arm. However, the authors noted that these data should be interpreted with caution because of the small number of deaths during the study.

“Together, these data support the notion that COPD is a systemic disease of accelerated aging and that replicative senescence, denoted by peripheral blood telomeres, is associated with poor health outcomes in COPD,” wrote Minhee Jin, of the University of British Columbia, Vancouver, and coauthors.

“It is now well established that replicative senescence results in a change of cellular phenotype to a proinflammatory state, a process that has been referred to as senescence-associated secretory phenotype,” they added.

The study also found that the median value for telomere length across the study participants – who had a mean age of 66 years – was equivalent to the expected value for someone in their 80s, “suggesting that on average MACRO participants were biologically much older than their chronological age.”

Researchers also noted that patients in the lowest quartile of telomere length had significantly lower forced vital capacity values, which suggested shorter telomeres could be a biomarker of restrictive physiology.

MACRO was funded by the U.S. National Heart, Lung, and Blood Institute, and the biomarker component of the study was funded by the Canadian Respiratory Research Network, Genome Canada, and the St. Paul’s Hospital Foundation. One author was an employee of GenomeDx Biosciences, three declared funding from or consultancies with the pharmaceutical industry. No other conflicts of interest were reported.

SOURCE: Jin M et al. Chest. 2018 Jul 12. doi: 10.1016/j.chest.2018.05.022.

Writing about prescribing psychotropics to children for depression, anxiety, or attention-deficit/hyperactivity disorder (ADHD) sometimes brings conspiratorial accusations from readers, pediatrician Perri Klass, MD, writes in her column, “The Checkup” in the New York Times.

Some readers react to these discussions by suggesting that Dr. Klass is beholden to pharmaceutical companies. Others suggest that she wants to medicate young patients for behaviors that are a normal part of childhood. Of course, prescribing those medications to young patients should never be taken lightly, she says.

“It is a big deal, and there are side effects to worry about and doctors should listen to families’ concerns,” writes Dr. Klass, professor of journalism and pediatrics at New York University. “But when a child is suffering and struggling, families need help and medications are often part of the discussion.”

Dr. Klass goes on to interview Doris M. Greenberg, MD, and psychiatrist Timothy Wilens, MD, about the way they approach the treatment of children with psychiatric illness. A critical step, according to Dr. Wilens, is discussing the diagnosis with the child’s parents and reaching an agreement with them on the problem.

Click here to read Dr. Klass’s article in the Times.
 

Writing about prescribing psychotropics to children for depression, anxiety, or attention-deficit/hyperactivity disorder (ADHD) sometimes brings conspiratorial accusations from readers, pediatrician Perri Klass, MD, writes in her column, “The Checkup” in the New York Times.

Some readers react to these discussions by suggesting that Dr. Klass is beholden to pharmaceutical companies. Others suggest that she wants to medicate young patients for behaviors that are a normal part of childhood. Of course, prescribing those medications to young patients should never be taken lightly, she says.

“It is a big deal, and there are side effects to worry about and doctors should listen to families’ concerns,” writes Dr. Klass, professor of journalism and pediatrics at New York University. “But when a child is suffering and struggling, families need help and medications are often part of the discussion.”

Dr. Klass goes on to interview Doris M. Greenberg, MD, and psychiatrist Timothy Wilens, MD, about the way they approach the treatment of children with psychiatric illness. A critical step, according to Dr. Wilens, is discussing the diagnosis with the child’s parents and reaching an agreement with them on the problem.

Click here to read Dr. Klass’s article in the Times.
 

Writing about prescribing psychotropics to children for depression, anxiety, or attention-deficit/hyperactivity disorder (ADHD) sometimes brings conspiratorial accusations from readers, pediatrician Perri Klass, MD, writes in her column, “The Checkup” in the New York Times.

Some readers react to these discussions by suggesting that Dr. Klass is beholden to pharmaceutical companies. Others suggest that she wants to medicate young patients for behaviors that are a normal part of childhood. Of course, prescribing those medications to young patients should never be taken lightly, she says.

“It is a big deal, and there are side effects to worry about and doctors should listen to families’ concerns,” writes Dr. Klass, professor of journalism and pediatrics at New York University. “But when a child is suffering and struggling, families need help and medications are often part of the discussion.”

Dr. Klass goes on to interview Doris M. Greenberg, MD, and psychiatrist Timothy Wilens, MD, about the way they approach the treatment of children with psychiatric illness. A critical step, according to Dr. Wilens, is discussing the diagnosis with the child’s parents and reaching an agreement with them on the problem.

Click here to read Dr. Klass’s article in the Times.
 

The Veterans Health Administration (VHA) provides health care services to over 9 million eligible and enrolled veterans out of a US veteran population of 18.9 million.¹ In 2014, an Office of Inspector General (OIG) investigation identified timely access to health care within the VHA as a serious concern.² In direct response, Congress enacted the Veterans Access, Choice, and Accountability Act (VACAA) of 2014 to expand access to care options available to veterans through referral to non-VA community care providers when the veteran is waiting longer than 30 days for an outpatient appointment or services, resides a significant distance (≥ 40 miles) from a VA facility, or experiences an undue burden to receive care and services.³ The VHA also responded, implementing several initiatives to improve veteran access to VHA health care generally, including the MyVA transformation and the proliferation of connected health technology; including telehealth capability and the expanded use of secure messaging. ^4-6

This study examined veterans’ access to the VA transplant program (VATP) for fiscal year (FY 2014 to FY 2016). Timeliness of services and outcomes in relationship to the distance from a VA transplant center (VATC) were evaluated.

Methods

The VATP comprises the following VATCs: 5 heart (Madison, Wisconsin; Nashville, Tennessee; Palo Alto, California; Richmond, Virginia; and Salt Lake City, Utah); 7 kidney (Birmingham, Alabama; Bronx, New York; Houston, Texas; Iowa City, Iowa; Nashville, Tennessee; Pittsburgh, Pennsylvania; and Portland, Oregon); 6 liver (Houston, Texas; Madison, Wisconsin; Nashville, Tennessee; Pittsburgh, Pennsylvania; Portland, Oregon; and Richmond, Virginia); and 2 lung (Madison, Wisconsin; and Seattle, Washington).

In 2012, the VHA published a policy to establish timeliness standards for a VATC initial review decision and referral evaluation.⁷ In 2013, the VHA National Surgery Office (NSO) implemented a secure intranet-based application called TRACER to facilitate the referral process and track timeliness of initial review decision, evaluation, United Network of Organ Sharing (UNOS) waitlisting, and transplantation.

The referral process is as follows: The referring VA medical facility submits veteran candidate health information into TRACER, selects a VATC, and then TRACER notifies the VATC. The VATC reviews the information and submits an initial review decision as to whether the clinical information supports further evaluation within 48 hours for an emergency referral and 5 business days for a stable referral. If accepted, the VATC completes an evaluation within 30 calendar days of the referral submission date. On evaluation and acceptance, the VATC accepts handoff for transplant-related care, orders additional testing as needed, and waitlists the veteran with UNOS when the clinical status is deemed appropriate.⁴

The TRACER data from 3 separate cohorts were analyzed from October 1, 2013, to September 30, 2016, with a follow-up event capture through March 31, 2017: (1) the referral cohort, representing all referrals to the VATP; (2) the waitlist cohort, representing those undergoing initial UNOS waitlisting; and (3) the transplant cohort, representing those receiving a solid organ transplant. The straight-line distance between the referring VA medical facility and the VATC was determined for each referral and categorized as follows: less than 100 miles, 100 to 300 miles, 301 to 500 miles, and greater than 500 miles.

Mortality outcomes in the TRACER database were confirmed using the VHA Vital Status file, which combines the Centers for Medicare & Medicaid Services, Social Security Administration, and VHA internal utilization data to determine a best source, including flagging of records that indicate a death date followed by use of VA services.^8,9 Records flagged with VA use after death were not considered deaths in this analysis. The NSO regularly refreshes veteran vital status information in the TRACER database for analysis of long-term outcomes.

The analysis methods for this study included Kruskall-Wallis nonparametric 1-way analysis of variance to compare timeliness metrics by distance group, Fine and Gray competing risks models to compare mortality on the UNOS list by distance group, and log-rank and Wilcoxon-Gehan tests to compare patient survival distributions by distance group.^10-14 Analysis was generated using SAS software, version 9.4 (Cary, North Carolina) as well as the R statistical software application (r-project.org).¹⁵ Publicly available solid organ transplant survival rates were obtained from the Scientific Registry for Transplant Recipients (SRTR).¹⁶

Results

For FY 2014 to FY 2016, the referral cohort identified 6,009 veteran referrals to a VATC for solid organ transplant of which 3,500 underwent an evaluation, and 2,137 were waitlisted for solid organ transplant with UNOS (Table 1). 

For the study period, 6,009 referrals resulted in 188 emergency initial review decisions and 3,551 stable initial review decisions with an eligible declaration (Table 2). 

Three thousand five hundred evaluations were performed in a median time of 27 calendar days (IQR 21-32 d) with 948 (27.1%) performed beyond the policy mandated 30 calendar days. Telehealth was used for 555 evaluations (15.9%), primarily for referrals located greater than 100 miles from the VATC. In FY 2016, 13.1% of the 1,321 completed evaluations were performed beyond 30 calendar days, representing an improvement from prior years; 45.7% beyond 30 calendar days in FY 2014 and 26.2% beyond 30 days in FY 2015.

Of the 6,009 referrals submitted in FY 2014 to FY 2016, 2,137 were waitlisted with UNOS. The median time from referral to waitlisting was 78 calendar days (IQR 43-148 d) for the entire study period, decreasing from 90 calendar days in FY 2014 to 70 calendar days in FY 2016.

For all organs and most organ types, the time from referral to initial review decision, evaluation, and waitlisting was statistically less (P < .005) for referrals received from VA medical facilities located less than 100 miles compared with referrals received from VA medical facilities at least 100 miles from the VATC. No statistical difference was found for emergency initial review decision for heart (P = .72) and lung (P = .14), time to evaluation for lung (P = .14), and time to waitlisting for heart (P = .95).

The waitlist cohort data are shown in Table 3. 

TRACER identified that 339 (15.0%) of the waitlist cohort were removed from the UNOS waitlist of which 212 (62.5%) were removed for failure to meet clinical criteria for transplantation, and 127 (37.5%) were removed for patient choice. Overall, 226 (10.0%) veterans died during the study period without receiving a transplant. Organ-specific mortality rates for veterans waitlisted but not transplanted at a VATC are as follows: heart 6.1%, kidney 5.9%, liver 19.0%, and lung 11.5%. As of March 31, 2017, 1,051 veterans were waitlisted with UNOS of which 876 (83.3%) were waitlisted for a kidney transplant.

The rate of mortality on the UNOS waitlist, the percentage of veterans transplanted, the time from waitlisting to transplantation, and the percentage of patients waitlisted at the end of the study period were not statistically different for referrals less than 100 miles compared with referrals at least 100 miles for all organs or kidney and liver separately (P ≤ .05). The relatively small numbers of veterans waitlisted for heart and lung transplants and nominal mortality events precluded making statements regarding significance for waitlist mortality.

The transplant cohort comprised 947 veterans receiving a solid organ transplant, including 102 (10.8%) heart, 411 (43.4%) kidney, 383 (40.4%) liver, and 51 (5.4%) lung transplants (Table 4). 

The transplant 30-day, 180-day, and 1-year survival rates are shown in Table 5. 

Discussion

This study shows that the VATP delivers timely, high-quality care and services even when the veteran’s referring VA medical facility is located a considerable distance from the VATC. Three separate cohorts of veterans were examined for the FY 2014 to FY 2016 study period: those referred, those waitlisted, and those transplanted. The referral cohort identified 6,009 referral submissions, performed 3,500 evaluations on veterans deemed to be potential candidates for solid organ transplantation, and placed 2,137 of these referrals on the UNOS waitlist. The median time from referral to initial review decision was 5 hours for emergency referrals and 3 business days for stable referrals. The median time from referral to evaluation was 27 calendar days, and the median time from referral to UNOS waitlisting was 78 calendar days. Improvements in timeliness for referral initial review decision, evaluation completion, and waitlisting over the study period were reflective of VHA and NSO efforts to enhance access to services. In FY 2016, 100% of emergency referrals received an initial review decision within 48 hours, 91.4% of stable reviews received an initial review decision within 5 business days, and 86.9% of all referrals underwent evaluation within 30 calendar days.

Distance of less than 100 miles between the referring VA medical facility and the VATC was associated with statistically significant shorter times for initial review decision, evaluation, and UNOS waitlisting. Referrals from less than 100 miles were a minority (9.6%) of referrals and most often represented a direct referral from the VATC to its own program. Timeliness of referral initial review decision, evaluation, or UNOS waitlisting was similar for distance categories greater than 100 miles: 100 to 300 miles, 301 to 500 miles, or greater than 500 miles.

The waitlist cohort identified 2,265 veterans, of which 731 (32.3%) underwent transplantation and 226 (10.0%) died. All-cause mortality for veterans once waitlisted, whether or not maintained on the UNOS waitlist, varied among organs and was found to be 6.1% for heart, 5.9% for kidney, 19.0% for liver, and 11.5% for lung. Waitlist mortality and the time from referral to solid organ transplant was similar for all distance categories.

The transplant cohort identified 947 veterans receiving a solid organ transplant with a median time from referral to transplant that varied considerably by organ type; 301 days (10.0 mo) for heart transplants, 914 days (30.5 mo) for kidney transplants, 236 days (7.9 mo) for liver transplants, and 246 days (8.2 mo) for lung transplants. Time to transplant and posttransplant survival were similar in all distance categories. Moreover, the VATP 1-year survival rates compared favorably with published SRTR data.

Prior studies have shown that distance to a transplant center adversely impacts access to transplant services, mortality on the UNOS waitlist, and transplant outcomes.^17-21 Patients living in small towns and isolated rural regions were 8% to 15% less likely to be waitlisted and 10% to 20% less likely to undergo heart, kidney, and liver transplantation than were patients in urban environments.¹⁷ This study found that a referral to the VATP from a VA medical facility located less than 100 miles from the VATC received an evaluation 5 to 7 days sooner and be placed on the UNOS waitlist 21 to 29 days sooner than a veteran referred to a VATC located at least 100 miles away. Contrary to prior studies, the distance from the VATC did not have an adverse impact on UNOS waitlist mortality, time to transplantation, or survival outcomes posttransplant.

The VHA offers a number of advantages to the veteran in need of transplant care and services. The VHA is the largest integrated health care system in the US designed specifically for veterans and their complex and specific needs with greater than 1,200 points of care and a single electronic health record optimizing coordinated services.²² In addition, the VHA’s use of telehealth to expedite evaluations and follow-up transplant care closer to home thereby obviating the need for travel. The VHA also has an electronic process to facilitate referral and tracking of timeliness of care (TRACER). Finally, VHA has policies that supports travel benefits, including lodging for the veteran, caregiver, and living donor if applicable for evaluations, transplant procedures, and follow-up care.^4,23

The coordination of health care services in a single integrated health care system may be the most significant advantage.²⁴ Multiple studies have examined dual care, representing care and services provided across 2 separate health care systems, showing an association between dual care and an increased risk of hospitalization, duplication of tests, rates for prescribing potentially unsafe medications, and mortality.^25-27 Although no study to date is on point, it is reasonable to imply that dual care imposes unnecessary risks to the veteran receiving complex lifelong transplant care when the VATP is shown to provide timely and high-quality care.

Limitations

The retrospective design and limited study period represent limitations. Specifically, survival outcomes for veterans transplanted were limited to 1 year and do not rule out the possibility that distance to a VATC will impact survival rates at 3 and 5 years posttransplant.

Conclusion

A referral distance of less than 100 miles from the VATC most often represents a direct referral and is a factor in timeliness of transplant initial review decision, evaluation, and placement of the veteran on the UNOS waitlist. Distance between the referring VA medical facility and the VATC, including distances of greater than 500 miles, was not found to impact the rate of mortality on the UNOS waitlist, time to transplantation, or posttransplant survival. Overall, the VHA provides timely solid organ transplant care and services with outcomes comparable to that of nationally reported SRTR estimates. Future studies should examine the timeliness of services, outcomes, and costs associated with those veterans authorized by the VHA for non-VA community care and those veterans who independently elect to receive transplant care and services by a non-VA transplant center and return to the VHA for dual care following transplantation.

The Veterans Health Administration (VHA) provides health care services to over 9 million eligible and enrolled veterans out of a US veteran population of 18.9 million.¹ In 2014, an Office of Inspector General (OIG) investigation identified timely access to health care within the VHA as a serious concern.² In direct response, Congress enacted the Veterans Access, Choice, and Accountability Act (VACAA) of 2014 to expand access to care options available to veterans through referral to non-VA community care providers when the veteran is waiting longer than 30 days for an outpatient appointment or services, resides a significant distance (≥ 40 miles) from a VA facility, or experiences an undue burden to receive care and services.³ The VHA also responded, implementing several initiatives to improve veteran access to VHA health care generally, including the MyVA transformation and the proliferation of connected health technology; including telehealth capability and the expanded use of secure messaging. ^4-6

This study examined veterans’ access to the VA transplant program (VATP) for fiscal year (FY 2014 to FY 2016). Timeliness of services and outcomes in relationship to the distance from a VA transplant center (VATC) were evaluated.

Methods

The VATP comprises the following VATCs: 5 heart (Madison, Wisconsin; Nashville, Tennessee; Palo Alto, California; Richmond, Virginia; and Salt Lake City, Utah); 7 kidney (Birmingham, Alabama; Bronx, New York; Houston, Texas; Iowa City, Iowa; Nashville, Tennessee; Pittsburgh, Pennsylvania; and Portland, Oregon); 6 liver (Houston, Texas; Madison, Wisconsin; Nashville, Tennessee; Pittsburgh, Pennsylvania; Portland, Oregon; and Richmond, Virginia); and 2 lung (Madison, Wisconsin; and Seattle, Washington).

In 2012, the VHA published a policy to establish timeliness standards for a VATC initial review decision and referral evaluation.⁷ In 2013, the VHA National Surgery Office (NSO) implemented a secure intranet-based application called TRACER to facilitate the referral process and track timeliness of initial review decision, evaluation, United Network of Organ Sharing (UNOS) waitlisting, and transplantation.

The referral process is as follows: The referring VA medical facility submits veteran candidate health information into TRACER, selects a VATC, and then TRACER notifies the VATC. The VATC reviews the information and submits an initial review decision as to whether the clinical information supports further evaluation within 48 hours for an emergency referral and 5 business days for a stable referral. If accepted, the VATC completes an evaluation within 30 calendar days of the referral submission date. On evaluation and acceptance, the VATC accepts handoff for transplant-related care, orders additional testing as needed, and waitlists the veteran with UNOS when the clinical status is deemed appropriate.⁴

The TRACER data from 3 separate cohorts were analyzed from October 1, 2013, to September 30, 2016, with a follow-up event capture through March 31, 2017: (1) the referral cohort, representing all referrals to the VATP; (2) the waitlist cohort, representing those undergoing initial UNOS waitlisting; and (3) the transplant cohort, representing those receiving a solid organ transplant. The straight-line distance between the referring VA medical facility and the VATC was determined for each referral and categorized as follows: less than 100 miles, 100 to 300 miles, 301 to 500 miles, and greater than 500 miles.

Mortality outcomes in the TRACER database were confirmed using the VHA Vital Status file, which combines the Centers for Medicare & Medicaid Services, Social Security Administration, and VHA internal utilization data to determine a best source, including flagging of records that indicate a death date followed by use of VA services.^8,9 Records flagged with VA use after death were not considered deaths in this analysis. The NSO regularly refreshes veteran vital status information in the TRACER database for analysis of long-term outcomes.

The analysis methods for this study included Kruskall-Wallis nonparametric 1-way analysis of variance to compare timeliness metrics by distance group, Fine and Gray competing risks models to compare mortality on the UNOS list by distance group, and log-rank and Wilcoxon-Gehan tests to compare patient survival distributions by distance group.^10-14 Analysis was generated using SAS software, version 9.4 (Cary, North Carolina) as well as the R statistical software application (r-project.org).¹⁵ Publicly available solid organ transplant survival rates were obtained from the Scientific Registry for Transplant Recipients (SRTR).¹⁶

Results

For FY 2014 to FY 2016, the referral cohort identified 6,009 veteran referrals to a VATC for solid organ transplant of which 3,500 underwent an evaluation, and 2,137 were waitlisted for solid organ transplant with UNOS (Table 1). 

For the study period, 6,009 referrals resulted in 188 emergency initial review decisions and 3,551 stable initial review decisions with an eligible declaration (Table 2). 

Three thousand five hundred evaluations were performed in a median time of 27 calendar days (IQR 21-32 d) with 948 (27.1%) performed beyond the policy mandated 30 calendar days. Telehealth was used for 555 evaluations (15.9%), primarily for referrals located greater than 100 miles from the VATC. In FY 2016, 13.1% of the 1,321 completed evaluations were performed beyond 30 calendar days, representing an improvement from prior years; 45.7% beyond 30 calendar days in FY 2014 and 26.2% beyond 30 days in FY 2015.

Of the 6,009 referrals submitted in FY 2014 to FY 2016, 2,137 were waitlisted with UNOS. The median time from referral to waitlisting was 78 calendar days (IQR 43-148 d) for the entire study period, decreasing from 90 calendar days in FY 2014 to 70 calendar days in FY 2016.

For all organs and most organ types, the time from referral to initial review decision, evaluation, and waitlisting was statistically less (P < .005) for referrals received from VA medical facilities located less than 100 miles compared with referrals received from VA medical facilities at least 100 miles from the VATC. No statistical difference was found for emergency initial review decision for heart (P = .72) and lung (P = .14), time to evaluation for lung (P = .14), and time to waitlisting for heart (P = .95).

The waitlist cohort data are shown in Table 3. 

TRACER identified that 339 (15.0%) of the waitlist cohort were removed from the UNOS waitlist of which 212 (62.5%) were removed for failure to meet clinical criteria for transplantation, and 127 (37.5%) were removed for patient choice. Overall, 226 (10.0%) veterans died during the study period without receiving a transplant. Organ-specific mortality rates for veterans waitlisted but not transplanted at a VATC are as follows: heart 6.1%, kidney 5.9%, liver 19.0%, and lung 11.5%. As of March 31, 2017, 1,051 veterans were waitlisted with UNOS of which 876 (83.3%) were waitlisted for a kidney transplant.

The rate of mortality on the UNOS waitlist, the percentage of veterans transplanted, the time from waitlisting to transplantation, and the percentage of patients waitlisted at the end of the study period were not statistically different for referrals less than 100 miles compared with referrals at least 100 miles for all organs or kidney and liver separately (P ≤ .05). The relatively small numbers of veterans waitlisted for heart and lung transplants and nominal mortality events precluded making statements regarding significance for waitlist mortality.

The transplant cohort comprised 947 veterans receiving a solid organ transplant, including 102 (10.8%) heart, 411 (43.4%) kidney, 383 (40.4%) liver, and 51 (5.4%) lung transplants (Table 4). 

The transplant 30-day, 180-day, and 1-year survival rates are shown in Table 5. 

Discussion

This study shows that the VATP delivers timely, high-quality care and services even when the veteran’s referring VA medical facility is located a considerable distance from the VATC. Three separate cohorts of veterans were examined for the FY 2014 to FY 2016 study period: those referred, those waitlisted, and those transplanted. The referral cohort identified 6,009 referral submissions, performed 3,500 evaluations on veterans deemed to be potential candidates for solid organ transplantation, and placed 2,137 of these referrals on the UNOS waitlist. The median time from referral to initial review decision was 5 hours for emergency referrals and 3 business days for stable referrals. The median time from referral to evaluation was 27 calendar days, and the median time from referral to UNOS waitlisting was 78 calendar days. Improvements in timeliness for referral initial review decision, evaluation completion, and waitlisting over the study period were reflective of VHA and NSO efforts to enhance access to services. In FY 2016, 100% of emergency referrals received an initial review decision within 48 hours, 91.4% of stable reviews received an initial review decision within 5 business days, and 86.9% of all referrals underwent evaluation within 30 calendar days.

Distance of less than 100 miles between the referring VA medical facility and the VATC was associated with statistically significant shorter times for initial review decision, evaluation, and UNOS waitlisting. Referrals from less than 100 miles were a minority (9.6%) of referrals and most often represented a direct referral from the VATC to its own program. Timeliness of referral initial review decision, evaluation, or UNOS waitlisting was similar for distance categories greater than 100 miles: 100 to 300 miles, 301 to 500 miles, or greater than 500 miles.

The waitlist cohort identified 2,265 veterans, of which 731 (32.3%) underwent transplantation and 226 (10.0%) died. All-cause mortality for veterans once waitlisted, whether or not maintained on the UNOS waitlist, varied among organs and was found to be 6.1% for heart, 5.9% for kidney, 19.0% for liver, and 11.5% for lung. Waitlist mortality and the time from referral to solid organ transplant was similar for all distance categories.

The transplant cohort identified 947 veterans receiving a solid organ transplant with a median time from referral to transplant that varied considerably by organ type; 301 days (10.0 mo) for heart transplants, 914 days (30.5 mo) for kidney transplants, 236 days (7.9 mo) for liver transplants, and 246 days (8.2 mo) for lung transplants. Time to transplant and posttransplant survival were similar in all distance categories. Moreover, the VATP 1-year survival rates compared favorably with published SRTR data.

Prior studies have shown that distance to a transplant center adversely impacts access to transplant services, mortality on the UNOS waitlist, and transplant outcomes.^17-21 Patients living in small towns and isolated rural regions were 8% to 15% less likely to be waitlisted and 10% to 20% less likely to undergo heart, kidney, and liver transplantation than were patients in urban environments.¹⁷ This study found that a referral to the VATP from a VA medical facility located less than 100 miles from the VATC received an evaluation 5 to 7 days sooner and be placed on the UNOS waitlist 21 to 29 days sooner than a veteran referred to a VATC located at least 100 miles away. Contrary to prior studies, the distance from the VATC did not have an adverse impact on UNOS waitlist mortality, time to transplantation, or survival outcomes posttransplant.

The VHA offers a number of advantages to the veteran in need of transplant care and services. The VHA is the largest integrated health care system in the US designed specifically for veterans and their complex and specific needs with greater than 1,200 points of care and a single electronic health record optimizing coordinated services.²² In addition, the VHA’s use of telehealth to expedite evaluations and follow-up transplant care closer to home thereby obviating the need for travel. The VHA also has an electronic process to facilitate referral and tracking of timeliness of care (TRACER). Finally, VHA has policies that supports travel benefits, including lodging for the veteran, caregiver, and living donor if applicable for evaluations, transplant procedures, and follow-up care.^4,23

The coordination of health care services in a single integrated health care system may be the most significant advantage.²⁴ Multiple studies have examined dual care, representing care and services provided across 2 separate health care systems, showing an association between dual care and an increased risk of hospitalization, duplication of tests, rates for prescribing potentially unsafe medications, and mortality.^25-27 Although no study to date is on point, it is reasonable to imply that dual care imposes unnecessary risks to the veteran receiving complex lifelong transplant care when the VATP is shown to provide timely and high-quality care.

Limitations

The retrospective design and limited study period represent limitations. Specifically, survival outcomes for veterans transplanted were limited to 1 year and do not rule out the possibility that distance to a VATC will impact survival rates at 3 and 5 years posttransplant.

Conclusion

A referral distance of less than 100 miles from the VATC most often represents a direct referral and is a factor in timeliness of transplant initial review decision, evaluation, and placement of the veteran on the UNOS waitlist. Distance between the referring VA medical facility and the VATC, including distances of greater than 500 miles, was not found to impact the rate of mortality on the UNOS waitlist, time to transplantation, or posttransplant survival. Overall, the VHA provides timely solid organ transplant care and services with outcomes comparable to that of nationally reported SRTR estimates. Future studies should examine the timeliness of services, outcomes, and costs associated with those veterans authorized by the VHA for non-VA community care and those veterans who independently elect to receive transplant care and services by a non-VA transplant center and return to the VHA for dual care following transplantation.

The Veterans Health Administration (VHA) provides health care services to over 9 million eligible and enrolled veterans out of a US veteran population of 18.9 million.¹ In 2014, an Office of Inspector General (OIG) investigation identified timely access to health care within the VHA as a serious concern.² In direct response, Congress enacted the Veterans Access, Choice, and Accountability Act (VACAA) of 2014 to expand access to care options available to veterans through referral to non-VA community care providers when the veteran is waiting longer than 30 days for an outpatient appointment or services, resides a significant distance (≥ 40 miles) from a VA facility, or experiences an undue burden to receive care and services.³ The VHA also responded, implementing several initiatives to improve veteran access to VHA health care generally, including the MyVA transformation and the proliferation of connected health technology; including telehealth capability and the expanded use of secure messaging. ^4-6

This study examined veterans’ access to the VA transplant program (VATP) for fiscal year (FY 2014 to FY 2016). Timeliness of services and outcomes in relationship to the distance from a VA transplant center (VATC) were evaluated.

Methods

The VATP comprises the following VATCs: 5 heart (Madison, Wisconsin; Nashville, Tennessee; Palo Alto, California; Richmond, Virginia; and Salt Lake City, Utah); 7 kidney (Birmingham, Alabama; Bronx, New York; Houston, Texas; Iowa City, Iowa; Nashville, Tennessee; Pittsburgh, Pennsylvania; and Portland, Oregon); 6 liver (Houston, Texas; Madison, Wisconsin; Nashville, Tennessee; Pittsburgh, Pennsylvania; Portland, Oregon; and Richmond, Virginia); and 2 lung (Madison, Wisconsin; and Seattle, Washington).

In 2012, the VHA published a policy to establish timeliness standards for a VATC initial review decision and referral evaluation.⁷ In 2013, the VHA National Surgery Office (NSO) implemented a secure intranet-based application called TRACER to facilitate the referral process and track timeliness of initial review decision, evaluation, United Network of Organ Sharing (UNOS) waitlisting, and transplantation.

The referral process is as follows: The referring VA medical facility submits veteran candidate health information into TRACER, selects a VATC, and then TRACER notifies the VATC. The VATC reviews the information and submits an initial review decision as to whether the clinical information supports further evaluation within 48 hours for an emergency referral and 5 business days for a stable referral. If accepted, the VATC completes an evaluation within 30 calendar days of the referral submission date. On evaluation and acceptance, the VATC accepts handoff for transplant-related care, orders additional testing as needed, and waitlists the veteran with UNOS when the clinical status is deemed appropriate.⁴

The TRACER data from 3 separate cohorts were analyzed from October 1, 2013, to September 30, 2016, with a follow-up event capture through March 31, 2017: (1) the referral cohort, representing all referrals to the VATP; (2) the waitlist cohort, representing those undergoing initial UNOS waitlisting; and (3) the transplant cohort, representing those receiving a solid organ transplant. The straight-line distance between the referring VA medical facility and the VATC was determined for each referral and categorized as follows: less than 100 miles, 100 to 300 miles, 301 to 500 miles, and greater than 500 miles.

Mortality outcomes in the TRACER database were confirmed using the VHA Vital Status file, which combines the Centers for Medicare & Medicaid Services, Social Security Administration, and VHA internal utilization data to determine a best source, including flagging of records that indicate a death date followed by use of VA services.^8,9 Records flagged with VA use after death were not considered deaths in this analysis. The NSO regularly refreshes veteran vital status information in the TRACER database for analysis of long-term outcomes.

The analysis methods for this study included Kruskall-Wallis nonparametric 1-way analysis of variance to compare timeliness metrics by distance group, Fine and Gray competing risks models to compare mortality on the UNOS list by distance group, and log-rank and Wilcoxon-Gehan tests to compare patient survival distributions by distance group.^10-14 Analysis was generated using SAS software, version 9.4 (Cary, North Carolina) as well as the R statistical software application (r-project.org).¹⁵ Publicly available solid organ transplant survival rates were obtained from the Scientific Registry for Transplant Recipients (SRTR).¹⁶

Results

For FY 2014 to FY 2016, the referral cohort identified 6,009 veteran referrals to a VATC for solid organ transplant of which 3,500 underwent an evaluation, and 2,137 were waitlisted for solid organ transplant with UNOS (Table 1). 

For the study period, 6,009 referrals resulted in 188 emergency initial review decisions and 3,551 stable initial review decisions with an eligible declaration (Table 2). 

Three thousand five hundred evaluations were performed in a median time of 27 calendar days (IQR 21-32 d) with 948 (27.1%) performed beyond the policy mandated 30 calendar days. Telehealth was used for 555 evaluations (15.9%), primarily for referrals located greater than 100 miles from the VATC. In FY 2016, 13.1% of the 1,321 completed evaluations were performed beyond 30 calendar days, representing an improvement from prior years; 45.7% beyond 30 calendar days in FY 2014 and 26.2% beyond 30 days in FY 2015.

Of the 6,009 referrals submitted in FY 2014 to FY 2016, 2,137 were waitlisted with UNOS. The median time from referral to waitlisting was 78 calendar days (IQR 43-148 d) for the entire study period, decreasing from 90 calendar days in FY 2014 to 70 calendar days in FY 2016.

For all organs and most organ types, the time from referral to initial review decision, evaluation, and waitlisting was statistically less (P < .005) for referrals received from VA medical facilities located less than 100 miles compared with referrals received from VA medical facilities at least 100 miles from the VATC. No statistical difference was found for emergency initial review decision for heart (P = .72) and lung (P = .14), time to evaluation for lung (P = .14), and time to waitlisting for heart (P = .95).

The waitlist cohort data are shown in Table 3. 

TRACER identified that 339 (15.0%) of the waitlist cohort were removed from the UNOS waitlist of which 212 (62.5%) were removed for failure to meet clinical criteria for transplantation, and 127 (37.5%) were removed for patient choice. Overall, 226 (10.0%) veterans died during the study period without receiving a transplant. Organ-specific mortality rates for veterans waitlisted but not transplanted at a VATC are as follows: heart 6.1%, kidney 5.9%, liver 19.0%, and lung 11.5%. As of March 31, 2017, 1,051 veterans were waitlisted with UNOS of which 876 (83.3%) were waitlisted for a kidney transplant.

The rate of mortality on the UNOS waitlist, the percentage of veterans transplanted, the time from waitlisting to transplantation, and the percentage of patients waitlisted at the end of the study period were not statistically different for referrals less than 100 miles compared with referrals at least 100 miles for all organs or kidney and liver separately (P ≤ .05). The relatively small numbers of veterans waitlisted for heart and lung transplants and nominal mortality events precluded making statements regarding significance for waitlist mortality.

The transplant cohort comprised 947 veterans receiving a solid organ transplant, including 102 (10.8%) heart, 411 (43.4%) kidney, 383 (40.4%) liver, and 51 (5.4%) lung transplants (Table 4). 

The transplant 30-day, 180-day, and 1-year survival rates are shown in Table 5. 

Discussion

This study shows that the VATP delivers timely, high-quality care and services even when the veteran’s referring VA medical facility is located a considerable distance from the VATC. Three separate cohorts of veterans were examined for the FY 2014 to FY 2016 study period: those referred, those waitlisted, and those transplanted. The referral cohort identified 6,009 referral submissions, performed 3,500 evaluations on veterans deemed to be potential candidates for solid organ transplantation, and placed 2,137 of these referrals on the UNOS waitlist. The median time from referral to initial review decision was 5 hours for emergency referrals and 3 business days for stable referrals. The median time from referral to evaluation was 27 calendar days, and the median time from referral to UNOS waitlisting was 78 calendar days. Improvements in timeliness for referral initial review decision, evaluation completion, and waitlisting over the study period were reflective of VHA and NSO efforts to enhance access to services. In FY 2016, 100% of emergency referrals received an initial review decision within 48 hours, 91.4% of stable reviews received an initial review decision within 5 business days, and 86.9% of all referrals underwent evaluation within 30 calendar days.

Distance of less than 100 miles between the referring VA medical facility and the VATC was associated with statistically significant shorter times for initial review decision, evaluation, and UNOS waitlisting. Referrals from less than 100 miles were a minority (9.6%) of referrals and most often represented a direct referral from the VATC to its own program. Timeliness of referral initial review decision, evaluation, or UNOS waitlisting was similar for distance categories greater than 100 miles: 100 to 300 miles, 301 to 500 miles, or greater than 500 miles.

The waitlist cohort identified 2,265 veterans, of which 731 (32.3%) underwent transplantation and 226 (10.0%) died. All-cause mortality for veterans once waitlisted, whether or not maintained on the UNOS waitlist, varied among organs and was found to be 6.1% for heart, 5.9% for kidney, 19.0% for liver, and 11.5% for lung. Waitlist mortality and the time from referral to solid organ transplant was similar for all distance categories.

The transplant cohort identified 947 veterans receiving a solid organ transplant with a median time from referral to transplant that varied considerably by organ type; 301 days (10.0 mo) for heart transplants, 914 days (30.5 mo) for kidney transplants, 236 days (7.9 mo) for liver transplants, and 246 days (8.2 mo) for lung transplants. Time to transplant and posttransplant survival were similar in all distance categories. Moreover, the VATP 1-year survival rates compared favorably with published SRTR data.

Prior studies have shown that distance to a transplant center adversely impacts access to transplant services, mortality on the UNOS waitlist, and transplant outcomes.^17-21 Patients living in small towns and isolated rural regions were 8% to 15% less likely to be waitlisted and 10% to 20% less likely to undergo heart, kidney, and liver transplantation than were patients in urban environments.¹⁷ This study found that a referral to the VATP from a VA medical facility located less than 100 miles from the VATC received an evaluation 5 to 7 days sooner and be placed on the UNOS waitlist 21 to 29 days sooner than a veteran referred to a VATC located at least 100 miles away. Contrary to prior studies, the distance from the VATC did not have an adverse impact on UNOS waitlist mortality, time to transplantation, or survival outcomes posttransplant.

The VHA offers a number of advantages to the veteran in need of transplant care and services. The VHA is the largest integrated health care system in the US designed specifically for veterans and their complex and specific needs with greater than 1,200 points of care and a single electronic health record optimizing coordinated services.²² In addition, the VHA’s use of telehealth to expedite evaluations and follow-up transplant care closer to home thereby obviating the need for travel. The VHA also has an electronic process to facilitate referral and tracking of timeliness of care (TRACER). Finally, VHA has policies that supports travel benefits, including lodging for the veteran, caregiver, and living donor if applicable for evaluations, transplant procedures, and follow-up care.^4,23

The coordination of health care services in a single integrated health care system may be the most significant advantage.²⁴ Multiple studies have examined dual care, representing care and services provided across 2 separate health care systems, showing an association between dual care and an increased risk of hospitalization, duplication of tests, rates for prescribing potentially unsafe medications, and mortality.^25-27 Although no study to date is on point, it is reasonable to imply that dual care imposes unnecessary risks to the veteran receiving complex lifelong transplant care when the VATP is shown to provide timely and high-quality care.

Limitations

The retrospective design and limited study period represent limitations. Specifically, survival outcomes for veterans transplanted were limited to 1 year and do not rule out the possibility that distance to a VATC will impact survival rates at 3 and 5 years posttransplant.

Conclusion

A referral distance of less than 100 miles from the VATC most often represents a direct referral and is a factor in timeliness of transplant initial review decision, evaluation, and placement of the veteran on the UNOS waitlist. Distance between the referring VA medical facility and the VATC, including distances of greater than 500 miles, was not found to impact the rate of mortality on the UNOS waitlist, time to transplantation, or posttransplant survival. Overall, the VHA provides timely solid organ transplant care and services with outcomes comparable to that of nationally reported SRTR estimates. Future studies should examine the timeliness of services, outcomes, and costs associated with those veterans authorized by the VHA for non-VA community care and those veterans who independently elect to receive transplant care and services by a non-VA transplant center and return to the VHA for dual care following transplantation.

The only 2 medicines currently approved for young people with type 2 diabetes—long-acting insulin and metformin—do not slow the progression of diabetes in young people, according to a study funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases.

A substudy of the Restoring Insulin Secretion (RISE) study, the RISE Pediatric Medication Study looked at the effects of insulin and metformin in 91 patients aged 10 to 19 years. The participants were randomly assigned to 1 of 2 treatment groups. The first received 3 months of glargine, a long-acting insulin, followed by 9 months of metformin. The second group received only metformin for 12 months. The participants were followed for 3 more months after treatment ended. The pediatric study found that beta-cell function declined in both groups during treatment and worsened after treatment ended.

Researchers also compared the pediatric participants with their adult counterparts in 2 other RISE trials and found the young people had more insulin resistance and other signs of disease progression at the same stage in the disease. Moreover, at baseline, the younger patients responded to the severe insulin resistance with a greater insulin response than did the adults, which the researchers say may be a reason for their more rapid loss of beta-cell function.

However, the study also found modest improvement in blood glucose with metformin in both groups. But metformin alone is not a long-term solution for many youth, said Dr. Kristen Nadeau, principal investigator for the pediatric study. Their findings underscore the “urgent and growing need,” she says, for more options.

The only 2 medicines currently approved for young people with type 2 diabetes—long-acting insulin and metformin—do not slow the progression of diabetes in young people, according to a study funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases.

A substudy of the Restoring Insulin Secretion (RISE) study, the RISE Pediatric Medication Study looked at the effects of insulin and metformin in 91 patients aged 10 to 19 years. The participants were randomly assigned to 1 of 2 treatment groups. The first received 3 months of glargine, a long-acting insulin, followed by 9 months of metformin. The second group received only metformin for 12 months. The participants were followed for 3 more months after treatment ended. The pediatric study found that beta-cell function declined in both groups during treatment and worsened after treatment ended.

Researchers also compared the pediatric participants with their adult counterparts in 2 other RISE trials and found the young people had more insulin resistance and other signs of disease progression at the same stage in the disease. Moreover, at baseline, the younger patients responded to the severe insulin resistance with a greater insulin response than did the adults, which the researchers say may be a reason for their more rapid loss of beta-cell function.

However, the study also found modest improvement in blood glucose with metformin in both groups. But metformin alone is not a long-term solution for many youth, said Dr. Kristen Nadeau, principal investigator for the pediatric study. Their findings underscore the “urgent and growing need,” she says, for more options.

The only 2 medicines currently approved for young people with type 2 diabetes—long-acting insulin and metformin—do not slow the progression of diabetes in young people, according to a study funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases.

A substudy of the Restoring Insulin Secretion (RISE) study, the RISE Pediatric Medication Study looked at the effects of insulin and metformin in 91 patients aged 10 to 19 years. The participants were randomly assigned to 1 of 2 treatment groups. The first received 3 months of glargine, a long-acting insulin, followed by 9 months of metformin. The second group received only metformin for 12 months. The participants were followed for 3 more months after treatment ended. The pediatric study found that beta-cell function declined in both groups during treatment and worsened after treatment ended.

Researchers also compared the pediatric participants with their adult counterparts in 2 other RISE trials and found the young people had more insulin resistance and other signs of disease progression at the same stage in the disease. Moreover, at baseline, the younger patients responded to the severe insulin resistance with a greater insulin response than did the adults, which the researchers say may be a reason for their more rapid loss of beta-cell function.

However, the study also found modest improvement in blood glucose with metformin in both groups. But metformin alone is not a long-term solution for many youth, said Dr. Kristen Nadeau, principal investigator for the pediatric study. Their findings underscore the “urgent and growing need,” she says, for more options.

Many patients with primary central nervous system lymphoma (PCNSL) experience rapid, aggressive progression of CNS malignancy. It is “accepted,” say researchers from Chonnam National University Hwasun Hospital in the Republic of Korea, that salvage therapy is beneficial and significantly improves survival in comparison to palliative care, but therapy options remain limited—mainly because few trials have been done. Several case reports have suggested that bendamustine has modest clinical activity against relapsed PCNSL, the researchers note, but its effect as part of combination salvage therapy in these patients has not been established. The study offers some validation of previous findings and new information about the benefits of a bendamustine-based combination regimen.

The researchers enrolled 10 patients, of whom 7 had refractory disease. All had previously been on high-dose methotrexate. Of the 3 relapsed patients, 1 entered the study at second relapse. The patients received either R-B(O)AD or R-BAD (rituximab, vincristine, bendamustine, cytarabine, dexamethasone) every 4 weeks for up to 4 cycles. Vincristine was omitted in 4 regimens, and dosages of bendamustine and cytarabine were reduced for 4 patients who were over 70.

The overall response rate for R-B(O)AD was 50%. One patient achieved complete response and 4 achieved partial response. The researchers observed “remarkable effects” on imaging in patients who responded. They attribute the activity to the anticipated synergy of bendamustine combined with cytarabine—even though disease in the majority of the patients had progressed despite previous treatment with cytarabine.

However, the synergistic effects also led to significant marrow depression; hematologic toxicity with R-B(O)AD was “considerable,” with grade 3 or 4 neutropenia and thrombocytopenia seen in more than 85% of treatment cycles. Moreover, 3 patients developed severe infection, all with involvement of the lungs. The researchers therefore amended the study protocol to reduce cytarabine dosage. While the toxicity is significant, the researchers say, it is manageable with the dose reduction and supportive care.

Bendamustine cerebrospinal fluid levels were minimal, but corresponded to plasma exposure and response to treatment in deep tumor locations.

Although the study is small, it supports the use of the bendamustine-based regimen as an effective salvage option, the researchers conclude, especially for patients who are no longer responding to methotrexate or have developed cumulative renal or neurotoxicity from treatment.

Source:
Kim T, Choi HY, Lee HS, et al. BMC Cancer. 2018;18(1):729

Many patients with primary central nervous system lymphoma (PCNSL) experience rapid, aggressive progression of CNS malignancy. It is “accepted,” say researchers from Chonnam National University Hwasun Hospital in the Republic of Korea, that salvage therapy is beneficial and significantly improves survival in comparison to palliative care, but therapy options remain limited—mainly because few trials have been done. Several case reports have suggested that bendamustine has modest clinical activity against relapsed PCNSL, the researchers note, but its effect as part of combination salvage therapy in these patients has not been established. The study offers some validation of previous findings and new information about the benefits of a bendamustine-based combination regimen.

The researchers enrolled 10 patients, of whom 7 had refractory disease. All had previously been on high-dose methotrexate. Of the 3 relapsed patients, 1 entered the study at second relapse. The patients received either R-B(O)AD or R-BAD (rituximab, vincristine, bendamustine, cytarabine, dexamethasone) every 4 weeks for up to 4 cycles. Vincristine was omitted in 4 regimens, and dosages of bendamustine and cytarabine were reduced for 4 patients who were over 70.

The overall response rate for R-B(O)AD was 50%. One patient achieved complete response and 4 achieved partial response. The researchers observed “remarkable effects” on imaging in patients who responded. They attribute the activity to the anticipated synergy of bendamustine combined with cytarabine—even though disease in the majority of the patients had progressed despite previous treatment with cytarabine.

However, the synergistic effects also led to significant marrow depression; hematologic toxicity with R-B(O)AD was “considerable,” with grade 3 or 4 neutropenia and thrombocytopenia seen in more than 85% of treatment cycles. Moreover, 3 patients developed severe infection, all with involvement of the lungs. The researchers therefore amended the study protocol to reduce cytarabine dosage. While the toxicity is significant, the researchers say, it is manageable with the dose reduction and supportive care.

Bendamustine cerebrospinal fluid levels were minimal, but corresponded to plasma exposure and response to treatment in deep tumor locations.

Although the study is small, it supports the use of the bendamustine-based regimen as an effective salvage option, the researchers conclude, especially for patients who are no longer responding to methotrexate or have developed cumulative renal or neurotoxicity from treatment.

Source:
Kim T, Choi HY, Lee HS, et al. BMC Cancer. 2018;18(1):729

Many patients with primary central nervous system lymphoma (PCNSL) experience rapid, aggressive progression of CNS malignancy. It is “accepted,” say researchers from Chonnam National University Hwasun Hospital in the Republic of Korea, that salvage therapy is beneficial and significantly improves survival in comparison to palliative care, but therapy options remain limited—mainly because few trials have been done. Several case reports have suggested that bendamustine has modest clinical activity against relapsed PCNSL, the researchers note, but its effect as part of combination salvage therapy in these patients has not been established. The study offers some validation of previous findings and new information about the benefits of a bendamustine-based combination regimen.

The researchers enrolled 10 patients, of whom 7 had refractory disease. All had previously been on high-dose methotrexate. Of the 3 relapsed patients, 1 entered the study at second relapse. The patients received either R-B(O)AD or R-BAD (rituximab, vincristine, bendamustine, cytarabine, dexamethasone) every 4 weeks for up to 4 cycles. Vincristine was omitted in 4 regimens, and dosages of bendamustine and cytarabine were reduced for 4 patients who were over 70.

The overall response rate for R-B(O)AD was 50%. One patient achieved complete response and 4 achieved partial response. The researchers observed “remarkable effects” on imaging in patients who responded. They attribute the activity to the anticipated synergy of bendamustine combined with cytarabine—even though disease in the majority of the patients had progressed despite previous treatment with cytarabine.

However, the synergistic effects also led to significant marrow depression; hematologic toxicity with R-B(O)AD was “considerable,” with grade 3 or 4 neutropenia and thrombocytopenia seen in more than 85% of treatment cycles. Moreover, 3 patients developed severe infection, all with involvement of the lungs. The researchers therefore amended the study protocol to reduce cytarabine dosage. While the toxicity is significant, the researchers say, it is manageable with the dose reduction and supportive care.

Bendamustine cerebrospinal fluid levels were minimal, but corresponded to plasma exposure and response to treatment in deep tumor locations.

Although the study is small, it supports the use of the bendamustine-based regimen as an effective salvage option, the researchers conclude, especially for patients who are no longer responding to methotrexate or have developed cumulative renal or neurotoxicity from treatment.

Source:
Kim T, Choi HY, Lee HS, et al. BMC Cancer. 2018;18(1):729

Photo courtesy of NHS

Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).

The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.

Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.

The researchers therefore believe this approach could be used to improve UCB transplants.

“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”

Dr Li and his colleagues conducted this research and described the work in Cell Research.

Past studies suggested that N⁶-methyladenosine (m⁶A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.

As the m⁶A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.

The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.

The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.

When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.

The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.

There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.

As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m⁶A-mediated mRNA decay.

The team discovered that m⁶A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.

“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.

“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”

Photo courtesy of NHS

Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).

The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.

Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.

The researchers therefore believe this approach could be used to improve UCB transplants.

“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”

Dr Li and his colleagues conducted this research and described the work in Cell Research.

Past studies suggested that N⁶-methyladenosine (m⁶A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.

As the m⁶A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.

The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.

The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.

When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.

The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.

There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.

As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m⁶A-mediated mRNA decay.

The team discovered that m⁶A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.

“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.

“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”

Photo courtesy of NHS

Researchers say they have discovered a new approach to expand hematopoietic stem cells (HSCs) from umbilical cord blood (UCB).

The team identified a protein, YTHDF2, that affects multiple targets and pathways involved in HSC self-renewal.

Experiments showed that reducing the function of YTHDF2 allowed UCB HSCs to expand.

The researchers therefore believe this approach could be used to improve UCB transplants.

“If we can expand cord adult stem cells, that could potentially decrease the number of cords needed per treatment,” said Linheng Li, PhD, of Stowers Institute for Medical Research in Kansas City, Missouri. “That’s a huge advantage.”

Dr Li and his colleagues conducted this research and described the work in Cell Research.

Past studies suggested that N⁶-methyladenosine (m⁶A) modulates the expression of a group of mRNAs that are critical for stem cell fate determination.

As the m⁶A reader YTHDF2 promotes targeted mRNA decay, Dr Li and his colleagues decided to target YTHDF2.

The researchers knocked out YTHDF2 function in a mouse model and observed an increase in functional HSCs. However, impairing YTHDF2 function did not alter lineage differentiation or lead to an increase in hematologic malignancies.

The researchers also knocked down YTHDF2 function in human UCB hematopoietic stem and progenitor cells. After 7 days of ex vivo culture, there was a roughly 14-fold increase in both the frequency and absolute number of HSCs with YTHDF2 knockdown (KD) cells compared to control cells.

When human UCB cells were transplanted into mice, there was a 9-fold increase in hematopoietic cell engraftment with YTHDF2 KD cells compared to control cells. In addition, the HSC frequency was about 4-fold higher in YTHDF2 KD cells.

The researchers transplanted bone marrow from primary recipient mice into sublethally irradiated secondary mice and found that, 12 weeks after transplant, human hematopoietic cell chimerism in the bone marrow was higher in YTHDF2 KD mice than in controls.

There was an 8-fold increase in competitive repopulating units from YTHDF2 KD cells compared to control cells.

As for why targeting YTHDF2 results in HSC expansion, the researchers found that YTHDF2 regulates HSC self-renewal gene expression by m⁶A-mediated mRNA decay.

The team discovered that m⁶A was enriched in mRNAs encoding transcription factors that are critical for stem cell self-renewal (such as GATA2, ETV6, STAT5, and TAL1). YTHDF2 recognizes these mRNAs and promotes their degradation.

“This work represents a path forward by demonstrating the ability to reliably expand adult stem cells from umbilical cord blood in the laboratory without terminally differentiating the cells into more mature and relatively short-lived blood cells,” said Joseph McGuirk, MD, a professor at the University of Kansas Health System who was not directly involved with this study.

“These findings represent a major advance in the field and have significant potential to improve the outcomes of thousands of children and adults who undergo umbilical cord blood transplantation every year.”

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo from Penn Medicine

Researchers have developed treatment guidelines for pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy.

The guidelines include recommendations for patient selection and consent, treatment details, and advice on managing cytokine release syndrome (CRS) and other adverse events associated with CAR T-cell therapy.

The guidelines were published in Nature Reviews Clinical Oncology.

“CAR T-cell therapy has been associated with remarkable response rates for children and young adults with ALL [acute lymphoblastic leukemia], yet this innovative form of cellular immunotherapy has resulted in unique and severe toxicities which can lead to rapid cardiorespiratory and/or neurological deterioration,” said guidelines author Kris Mahadeo, MD, of The University of Texas MD Anderson Cancer Center in Houston.

“This novel therapy requires the medical vigilance of a diverse multi-disciplinary team and associated clinical infrastructure to ensure optimal patient outcomes.”

Pediatric patient selection and consent

The guidelines state that providers of CAR T-cell therapies should adhere to product information labels and guidance from risk evaluation and mitigation strategy programs (level of evidence: IV, grade: D).

In addition, patient selection should be based on the indications approved by the US Food and Drug Administration and criteria used in pivotal studies. However, this can change as new information becomes available (level of evidence: IV, grade: D).

Informed consent should include descriptions of the risks and benefits associated with leukapheresis, lymphodepletion, CRS, CAR T-cell-related encephalopathy syndrome (CRES), bridging chemotherapy, intensive care support, and anti-IL-6 therapy (level of evidence: IIA, grade: B).

Providers should obtain child assent when appropriate and may benefit from incorporating child life and psychological services in assent discussions (level of evidence: IV, grade: D).

Treatment specifics

The guidelines recommend cyclophosphamide–fludarabine regimens for lymphodepletion, although exceptions can be considered in cases of hemorrhagic cystitis and/or resistance to a prior cyclophosphamide-based regimen (level of evidence: IIA, grade: B).

Providers should consider inpatient admission for a minimum of 3 to 7 days after receipt of tisagenlecleucel. This was based on the experience in pediatric and young adult patients with CD19+ relapsed and/or refractory B-cell acute lymphoblastic leukemia (level of evidence: IIA, grade: B).

Patients should be closely monitored for hypotension, hypocalcemia, and catheter-related pain during leukapheresis (level of evidence: IIA, grade: B).

For patients receiving tocilizumab, those weighing <30 kg should receive 12 mg/kg, and those weighing ≥30 kg should receive 8 mg/kg (level of evidence: IIA, grade: B).

Adverse events

The guidelines say parent and/or caregiver concerns should be addressed as these individuals may be best equipped to recognize early signs or symptoms of CRS (level of evidence: III, grade: C).

When CAR T-cell therapy is administered in an outpatient setting, there should be a low threshold for patient admission upon the development of signs or symptoms suggestive of CRS and/or CRES (level of evidence: IIA, grade: B).

CRS grading should be performed at least once every 12 hours (level of evidence: IIA, grade: B). Detailed information on grading is provided in the guidelines.

Providers should suspect CRS if any of the following signs/symptoms are present within the first 2 weeks of CAR T-cell infusion:

• Fever ≥38 °C
• Hypotension
• Hypoxia with an arterial oxygen saturation of <90% on room air
• Evidence of organ toxicity as determined by the most recent CTCAE grading system and considerations detailed in the guidelines (level of evidence: IIA, grade: C).

The guidelines also recommend “high vigilance” for sinus tachycardia as an early sign of CRS (level of evidence: IIA, grade: B) as well as application of the PALICC (Pediatric Acute Lung Injury Consensus Conference) at-risk P-ARDS (pediatric acute respiratory distress syndrome) criteria for the CRS grading of hypoxia (level of evidence: IIA, grade: B).

Hemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome can be treated with anti-IL-6 therapy and corticosteroids. However, refractory cases may require systemic and/or intrathecal therapy or use of the IL-1 receptor antagonist anakinra (level of evidence: IIA, grade: C).

The guidelines recommend that delirium screening be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES (level of evidence: IIA, grade: C). Delirium screening should be performed with the CAPD (Cornell Assessment of Pediatric Delirium) tool or CARTOX-10 (CAR T-Cell Therapy-Associated Toxicity 10-point assessment scale) for patients age 12 and older who have sufficient cognitive abilities.

Acute kidney injury in children can be graded according to the CTCAE (Common Terminology Criteria for Adverse Events) using pRIFLE (Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease) and KDIGO (Kidney Disease: Improving Global Outcomes) definitions of oliguria (level of evidence: IIA, grade: B).

Other considerations

The guidelines “strongly encourage” consideration of quality-adjusted life-years gained for pediatric patients who might achieve long-term remission from CAR T-cell therapy and encourage efforts to reduce the cost of care (level of evidence: IV, grade: D).

The guidelines also recommend that CAR T-cell programs seek FACT IEC (Foundation for the Accreditation of Cellular Therapy for Immune Effector Cells) accreditation to ensure adherence to quality standards (level of evidence: IV, grade: D).

Finally, the guidelines suggest the possibility of a prospective collaboration with intensive-care registries, which could allow accurate data entry of cell therapy variables into the CIBMTR registry with concurrent entry of intensive-care variables into an appropriate registry by pediatric critical care teams (level of evidence: IV, grade: D).

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) is warning against long-term use of azithromycin (Zithromax, Zmax) in patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT).

Azithromycin has been used off-label as prophylaxis for bronchiolitis obliterans syndrome in these patients.

However, a trial published in JAMA last year suggested that long-term azithromycin use increases the risk of relapse and death in patients undergoing allo-HSCT as treatment for hematologic malignancies.

The FDA said it is reviewing additional data and will communicate its conclusions and recommendations when the review is complete.

In the meantime, the agency said healthcare professionals should not prescribe long-term azithromycin to allo-HSCT recipients for prophylaxis of bronchiolitis obliterans syndrome. However, patients should not stop taking azithromycin without first consulting their healthcare professionals.

Healthcare professionals and patients can report adverse events related to azithromycin to the FDA’s MedWatch program.

Pfizer, which markets Zithromax, has issued a Dear Healthcare Provider letter warning about the risks of relapse and death associated with long-term azithromycin use in allo-HSCT recipients.

The company said there is no evidence to suggest increased risks in other patient populations or when azithromycin is used for FDA-approved indications.

It isn’t clear why allo-HSCT recipients may have an increased risk of relapse/death with long-term azithromycin use. However, Pfizer said the available evidence raises questions about the safety of prophylactic azithromycin in this patient population, suggesting the risks outweigh the benefits.

The evidence comes from the ALLOZITHRO trial, which was published in JAMA in August 2017.

The trial included 480 patients who had undergone allo-HSCT for a hematologic malignancy. They were randomized to receive 250 mg of azithromycin (n=243) or placebo (n=237) 3 times a week for 2 years, beginning at the start of conditioning.

The trial was stopped about 13 months after enrollment was completed because there was an unexpected increase in the rate of relapse and death in patients taking azithromycin.

The 2-year cumulative incidence of relapse was 33.5% in the azithromycin group and 22.3% in the placebo group (unadjusted cause-specific hazard ratio [HR]=1.7, P=0.002).

The 2-year survival rate was 56.6% in the azithromycin group and 70.1% in the placebo group (adjusted HR=1.5, P=0.02).

The 2-year airflow decline-free survival rate was 32.8% in the azithromycin group and 41.3% in the placebo group (unadjusted HR=1.3, P=0.03).

And the incidence of bronchiolitis obliterans syndrome was 6% in the azithromycin group and 3% in the placebo group (P=0.08).

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) is warning against long-term use of azithromycin (Zithromax, Zmax) in patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT).

Azithromycin has been used off-label as prophylaxis for bronchiolitis obliterans syndrome in these patients.

However, a trial published in JAMA last year suggested that long-term azithromycin use increases the risk of relapse and death in patients undergoing allo-HSCT as treatment for hematologic malignancies.

The FDA said it is reviewing additional data and will communicate its conclusions and recommendations when the review is complete.

In the meantime, the agency said healthcare professionals should not prescribe long-term azithromycin to allo-HSCT recipients for prophylaxis of bronchiolitis obliterans syndrome. However, patients should not stop taking azithromycin without first consulting their healthcare professionals.

Healthcare professionals and patients can report adverse events related to azithromycin to the FDA’s MedWatch program.

Pfizer, which markets Zithromax, has issued a Dear Healthcare Provider letter warning about the risks of relapse and death associated with long-term azithromycin use in allo-HSCT recipients.

The company said there is no evidence to suggest increased risks in other patient populations or when azithromycin is used for FDA-approved indications.

It isn’t clear why allo-HSCT recipients may have an increased risk of relapse/death with long-term azithromycin use. However, Pfizer said the available evidence raises questions about the safety of prophylactic azithromycin in this patient population, suggesting the risks outweigh the benefits.

The evidence comes from the ALLOZITHRO trial, which was published in JAMA in August 2017.

The trial included 480 patients who had undergone allo-HSCT for a hematologic malignancy. They were randomized to receive 250 mg of azithromycin (n=243) or placebo (n=237) 3 times a week for 2 years, beginning at the start of conditioning.

The trial was stopped about 13 months after enrollment was completed because there was an unexpected increase in the rate of relapse and death in patients taking azithromycin.

The 2-year cumulative incidence of relapse was 33.5% in the azithromycin group and 22.3% in the placebo group (unadjusted cause-specific hazard ratio [HR]=1.7, P=0.002).

The 2-year survival rate was 56.6% in the azithromycin group and 70.1% in the placebo group (adjusted HR=1.5, P=0.02).

The 2-year airflow decline-free survival rate was 32.8% in the azithromycin group and 41.3% in the placebo group (unadjusted HR=1.3, P=0.03).

And the incidence of bronchiolitis obliterans syndrome was 6% in the azithromycin group and 3% in the placebo group (P=0.08).

Photo by Chad McNeeley

The US Food and Drug Administration (FDA) is warning against long-term use of azithromycin (Zithromax, Zmax) in patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT).

Azithromycin has been used off-label as prophylaxis for bronchiolitis obliterans syndrome in these patients.

However, a trial published in JAMA last year suggested that long-term azithromycin use increases the risk of relapse and death in patients undergoing allo-HSCT as treatment for hematologic malignancies.

The FDA said it is reviewing additional data and will communicate its conclusions and recommendations when the review is complete.

In the meantime, the agency said healthcare professionals should not prescribe long-term azithromycin to allo-HSCT recipients for prophylaxis of bronchiolitis obliterans syndrome. However, patients should not stop taking azithromycin without first consulting their healthcare professionals.

Healthcare professionals and patients can report adverse events related to azithromycin to the FDA’s MedWatch program.

Pfizer, which markets Zithromax, has issued a Dear Healthcare Provider letter warning about the risks of relapse and death associated with long-term azithromycin use in allo-HSCT recipients.

The company said there is no evidence to suggest increased risks in other patient populations or when azithromycin is used for FDA-approved indications.

It isn’t clear why allo-HSCT recipients may have an increased risk of relapse/death with long-term azithromycin use. However, Pfizer said the available evidence raises questions about the safety of prophylactic azithromycin in this patient population, suggesting the risks outweigh the benefits.

The evidence comes from the ALLOZITHRO trial, which was published in JAMA in August 2017.

The trial included 480 patients who had undergone allo-HSCT for a hematologic malignancy. They were randomized to receive 250 mg of azithromycin (n=243) or placebo (n=237) 3 times a week for 2 years, beginning at the start of conditioning.

The trial was stopped about 13 months after enrollment was completed because there was an unexpected increase in the rate of relapse and death in patients taking azithromycin.

The 2-year cumulative incidence of relapse was 33.5% in the azithromycin group and 22.3% in the placebo group (unadjusted cause-specific hazard ratio [HR]=1.7, P=0.002).

The 2-year survival rate was 56.6% in the azithromycin group and 70.1% in the placebo group (adjusted HR=1.5, P=0.02).

The 2-year airflow decline-free survival rate was 32.8% in the azithromycin group and 41.3% in the placebo group (unadjusted HR=1.3, P=0.03).

And the incidence of bronchiolitis obliterans syndrome was 6% in the azithromycin group and 3% in the placebo group (P=0.08).

ANSWER

The chest radiograph shows an approximately 3-cm cavitary lesion in the right upper lobe. Such a lesion can indicate lung abscess, neoplasm, or tuberculosis. 

Subsequent workup determined that he did, in fact, have tuberculosis, with involvement in his spine (known as Pott disease).

ANSWER

The chest radiograph shows an approximately 3-cm cavitary lesion in the right upper lobe. Such a lesion can indicate lung abscess, neoplasm, or tuberculosis. 

Subsequent workup determined that he did, in fact, have tuberculosis, with involvement in his spine (known as Pott disease).

ANSWER

The chest radiograph shows an approximately 3-cm cavitary lesion in the right upper lobe. Such a lesion can indicate lung abscess, neoplasm, or tuberculosis. 

Subsequent workup determined that he did, in fact, have tuberculosis, with involvement in his spine (known as Pott disease).