In an attempt to reduce the rate and cost of complications following hip and knee replacements among Medicare beneficiaries, the Centers for Medicare & Medicaid Services (CMS) announced a new Comprehensive Care for Joint Replacement payment model. With this new measure, the CMS proposes to hold hospitals accountable for the quality of care they deliver to Medicare fee-for-service beneficiaries for hip and knee replacements from surgery through recovery.

“We are committed to changing our health care system to pay for quality over quantity, so that we spend our dollars more wisely and improve care for patients,” said Sylvia M. Burwell, Secretary of Health and Human Services.

Through the proposed 5-year payment model, health care providers in 75 geographic areas would continue to be paid under existing Medicare payment systems. However, the hospital where the hip or knee replacement is performed would be held liable for the quality and costs of care for the duration of care, from the time of the surgery through 90 days after discharge.

Depending on the hospital’s quality and cost performance during the episode, the hospital may receive an additional payment or be required to repay Medicare for a portion of the episode costs. As a result, hospitals would have an incentive to work with physicians, home health agencies, and nursing facilities to ensure that beneficiaries receive the coordinated care they need, with the goal of reducing avoidable hospitalizations and complications. Hospitals would receive tools, such as spending and utilization data and sharing of best practices, to improve the effectiveness of care coordination.

These bundled payments for joint replacement surgeries would build upon successful demonstration programs already underway in Medicare. This model is also consistent with the private sector, where major employers and leading providers and care systems are moving towards bundled payments for orthopedic services.

“Today, we are taking another important step to improve the quality of care for the hundreds of thousands of Americans who have hip and knee replacements through Medicare every year. By focusing on episodes of care, rather than a piecemeal system, hospitals and physicians have an incentive to work together to deliver more effective and efficient care. This model will incentivize providing patients with the right care the first time and finding better ways to help them recover successfully. It will reward providers and doctors for helping patients get and stay healthy, ” stated Ms. Burwell.

In an attempt to reduce the rate and cost of complications following hip and knee replacements among Medicare beneficiaries, the Centers for Medicare & Medicaid Services (CMS) announced a new Comprehensive Care for Joint Replacement payment model. With this new measure, the CMS proposes to hold hospitals accountable for the quality of care they deliver to Medicare fee-for-service beneficiaries for hip and knee replacements from surgery through recovery.

“We are committed to changing our health care system to pay for quality over quantity, so that we spend our dollars more wisely and improve care for patients,” said Sylvia M. Burwell, Secretary of Health and Human Services.

Through the proposed 5-year payment model, health care providers in 75 geographic areas would continue to be paid under existing Medicare payment systems. However, the hospital where the hip or knee replacement is performed would be held liable for the quality and costs of care for the duration of care, from the time of the surgery through 90 days after discharge.

Depending on the hospital’s quality and cost performance during the episode, the hospital may receive an additional payment or be required to repay Medicare for a portion of the episode costs. As a result, hospitals would have an incentive to work with physicians, home health agencies, and nursing facilities to ensure that beneficiaries receive the coordinated care they need, with the goal of reducing avoidable hospitalizations and complications. Hospitals would receive tools, such as spending and utilization data and sharing of best practices, to improve the effectiveness of care coordination.

These bundled payments for joint replacement surgeries would build upon successful demonstration programs already underway in Medicare. This model is also consistent with the private sector, where major employers and leading providers and care systems are moving towards bundled payments for orthopedic services.

“Today, we are taking another important step to improve the quality of care for the hundreds of thousands of Americans who have hip and knee replacements through Medicare every year. By focusing on episodes of care, rather than a piecemeal system, hospitals and physicians have an incentive to work together to deliver more effective and efficient care. This model will incentivize providing patients with the right care the first time and finding better ways to help them recover successfully. It will reward providers and doctors for helping patients get and stay healthy, ” stated Ms. Burwell.

In an attempt to reduce the rate and cost of complications following hip and knee replacements among Medicare beneficiaries, the Centers for Medicare & Medicaid Services (CMS) announced a new Comprehensive Care for Joint Replacement payment model. With this new measure, the CMS proposes to hold hospitals accountable for the quality of care they deliver to Medicare fee-for-service beneficiaries for hip and knee replacements from surgery through recovery.

“We are committed to changing our health care system to pay for quality over quantity, so that we spend our dollars more wisely and improve care for patients,” said Sylvia M. Burwell, Secretary of Health and Human Services.

Through the proposed 5-year payment model, health care providers in 75 geographic areas would continue to be paid under existing Medicare payment systems. However, the hospital where the hip or knee replacement is performed would be held liable for the quality and costs of care for the duration of care, from the time of the surgery through 90 days after discharge.

Depending on the hospital’s quality and cost performance during the episode, the hospital may receive an additional payment or be required to repay Medicare for a portion of the episode costs. As a result, hospitals would have an incentive to work with physicians, home health agencies, and nursing facilities to ensure that beneficiaries receive the coordinated care they need, with the goal of reducing avoidable hospitalizations and complications. Hospitals would receive tools, such as spending and utilization data and sharing of best practices, to improve the effectiveness of care coordination.

These bundled payments for joint replacement surgeries would build upon successful demonstration programs already underway in Medicare. This model is also consistent with the private sector, where major employers and leading providers and care systems are moving towards bundled payments for orthopedic services.

“Today, we are taking another important step to improve the quality of care for the hundreds of thousands of Americans who have hip and knee replacements through Medicare every year. By focusing on episodes of care, rather than a piecemeal system, hospitals and physicians have an incentive to work together to deliver more effective and efficient care. This model will incentivize providing patients with the right care the first time and finding better ways to help them recover successfully. It will reward providers and doctors for helping patients get and stay healthy, ” stated Ms. Burwell.

Presenters: Nichole Chandler MD, Suresh Nagappan MD MSPH, Angela Hartsell MD MPH, and Emily Hodnett MD

This workshop focused on interactive cases to highlight healthcare issues specific to the population of refugee/immigrant children in the US. It was an interactive format with small groups to allow the participants to work through the diagnoses by discovery. The cases included a Burmese infant with macrocephaly due to congenital toxoplasmosis and a school-age Eritrean child with abdominal pain due to Plasmodium vivax malaria. In addition to discussing the clinical presentation and work up of the patients, there were accompanying ethical dilemmas that were a part of taking care these patients. The presenters emphasized the importance of culturally sensitive communication and seeking competent translation for key clinical discussions. At the end, they supplied a list of resources for more information on refugees in the US and refugee healthcare.

Bethany Hodge MD MPH

Just for Kids Pediatric Hospitalists, Kosair Children’s Hospital

Assistant professor, Department of Pediatrics

Director of the Distinction in Global Health Track

University of Louisville School of Medicine

Presenters: Nichole Chandler MD, Suresh Nagappan MD MSPH, Angela Hartsell MD MPH, and Emily Hodnett MD

This workshop focused on interactive cases to highlight healthcare issues specific to the population of refugee/immigrant children in the US. It was an interactive format with small groups to allow the participants to work through the diagnoses by discovery. The cases included a Burmese infant with macrocephaly due to congenital toxoplasmosis and a school-age Eritrean child with abdominal pain due to Plasmodium vivax malaria. In addition to discussing the clinical presentation and work up of the patients, there were accompanying ethical dilemmas that were a part of taking care these patients. The presenters emphasized the importance of culturally sensitive communication and seeking competent translation for key clinical discussions. At the end, they supplied a list of resources for more information on refugees in the US and refugee healthcare.

Bethany Hodge MD MPH

Just for Kids Pediatric Hospitalists, Kosair Children’s Hospital

Assistant professor, Department of Pediatrics

Director of the Distinction in Global Health Track

University of Louisville School of Medicine

Presenters: Nichole Chandler MD, Suresh Nagappan MD MSPH, Angela Hartsell MD MPH, and Emily Hodnett MD

This workshop focused on interactive cases to highlight healthcare issues specific to the population of refugee/immigrant children in the US. It was an interactive format with small groups to allow the participants to work through the diagnoses by discovery. The cases included a Burmese infant with macrocephaly due to congenital toxoplasmosis and a school-age Eritrean child with abdominal pain due to Plasmodium vivax malaria. In addition to discussing the clinical presentation and work up of the patients, there were accompanying ethical dilemmas that were a part of taking care these patients. The presenters emphasized the importance of culturally sensitive communication and seeking competent translation for key clinical discussions. At the end, they supplied a list of resources for more information on refugees in the US and refugee healthcare.

Bethany Hodge MD MPH

Just for Kids Pediatric Hospitalists, Kosair Children’s Hospital

Assistant professor, Department of Pediatrics

Director of the Distinction in Global Health Track

University of Louisville School of Medicine

Lab mice

Photo by Aaron Logan

Preclinical research has revealed potential therapeutic options for TCF3-HLF-positive acute lymphoblastic leukemia (ALL).

Investigators discovered a range of mutations in this subtype of ALL and identified features that appear to contribute to treatment resistance.

However, the team also found that TCF3-HLF-positive ALL is sensitive to treatment with glucocorticoids, anthracyclines, and certain agents in clinical development.

The BCL2-specific inhibitor venetoclax (ABT-199) proved particularly active against the disease.

Jean-Pierre Bourquin, MD, PhD, of the University Children’s Hospital Zurich in Switzerland, and his colleagues reported these findings in Nature Genetics.

The investigators sequenced samples from patients with TCF3-HLF-positive ALL and found a range of mutations. Most samples (67%) had deletions in PAX5, and most of the samples without PAX5 deletions had deletions in VPREB1.

The team also found recurrent mutations of TCF3, a new fusion gene (KHDRBS1-LCK), and activating mutations in RAS signaling pathway genes (NRAS, KRAS, and PTPN11), among other mutations.

After additional investigation, Dr Bourquin and his colleagues hypothesized that the initiating TCF3-HLF fusion in this disease occurs in a B-cell progenitor, and the specific lineage context is constrained further in a restricted developmental stage by additional mutations.

The investigators also tested various treatments in mouse models of TCF3-HLF-positive ALL. They observed resistance to dasatinib, nucleotide analogs, mitotic spindle inhibitors, and polo-like and aurora kinase inhibitors.

On the other hand, the disease was sensitive to glucocorticoids, mTOR inhibitors, anthracyclines, bortezomib, the HSP90 inhibitor AUY922, and panobinostat.

The team also found evidence suggesting that BCL2 might promote leukemic cell survival and constitute a druggable target in TCF3-HLF-positive ALL. So they tested the BCL2 inhibitor venetoclax in the mice.

A 2-week course of daily venetoclax significantly delayed leukemia progression, and xenografts from relapsed patients and those with minimal residual disease remained sensitive to venetoclax. The drug also exhibited synergistic effects when combined with vincristine or dexamethasone.

“Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” Dr Bourquin concluded.

Lab mice

Photo by Aaron Logan

Preclinical research has revealed potential therapeutic options for TCF3-HLF-positive acute lymphoblastic leukemia (ALL).

Investigators discovered a range of mutations in this subtype of ALL and identified features that appear to contribute to treatment resistance.

However, the team also found that TCF3-HLF-positive ALL is sensitive to treatment with glucocorticoids, anthracyclines, and certain agents in clinical development.

The BCL2-specific inhibitor venetoclax (ABT-199) proved particularly active against the disease.

Jean-Pierre Bourquin, MD, PhD, of the University Children’s Hospital Zurich in Switzerland, and his colleagues reported these findings in Nature Genetics.

The investigators sequenced samples from patients with TCF3-HLF-positive ALL and found a range of mutations. Most samples (67%) had deletions in PAX5, and most of the samples without PAX5 deletions had deletions in VPREB1.

The team also found recurrent mutations of TCF3, a new fusion gene (KHDRBS1-LCK), and activating mutations in RAS signaling pathway genes (NRAS, KRAS, and PTPN11), among other mutations.

After additional investigation, Dr Bourquin and his colleagues hypothesized that the initiating TCF3-HLF fusion in this disease occurs in a B-cell progenitor, and the specific lineage context is constrained further in a restricted developmental stage by additional mutations.

The investigators also tested various treatments in mouse models of TCF3-HLF-positive ALL. They observed resistance to dasatinib, nucleotide analogs, mitotic spindle inhibitors, and polo-like and aurora kinase inhibitors.

On the other hand, the disease was sensitive to glucocorticoids, mTOR inhibitors, anthracyclines, bortezomib, the HSP90 inhibitor AUY922, and panobinostat.

The team also found evidence suggesting that BCL2 might promote leukemic cell survival and constitute a druggable target in TCF3-HLF-positive ALL. So they tested the BCL2 inhibitor venetoclax in the mice.

A 2-week course of daily venetoclax significantly delayed leukemia progression, and xenografts from relapsed patients and those with minimal residual disease remained sensitive to venetoclax. The drug also exhibited synergistic effects when combined with vincristine or dexamethasone.

“Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” Dr Bourquin concluded.

Lab mice

Photo by Aaron Logan

Preclinical research has revealed potential therapeutic options for TCF3-HLF-positive acute lymphoblastic leukemia (ALL).

Investigators discovered a range of mutations in this subtype of ALL and identified features that appear to contribute to treatment resistance.

However, the team also found that TCF3-HLF-positive ALL is sensitive to treatment with glucocorticoids, anthracyclines, and certain agents in clinical development.

The BCL2-specific inhibitor venetoclax (ABT-199) proved particularly active against the disease.

Jean-Pierre Bourquin, MD, PhD, of the University Children’s Hospital Zurich in Switzerland, and his colleagues reported these findings in Nature Genetics.

The investigators sequenced samples from patients with TCF3-HLF-positive ALL and found a range of mutations. Most samples (67%) had deletions in PAX5, and most of the samples without PAX5 deletions had deletions in VPREB1.

The team also found recurrent mutations of TCF3, a new fusion gene (KHDRBS1-LCK), and activating mutations in RAS signaling pathway genes (NRAS, KRAS, and PTPN11), among other mutations.

After additional investigation, Dr Bourquin and his colleagues hypothesized that the initiating TCF3-HLF fusion in this disease occurs in a B-cell progenitor, and the specific lineage context is constrained further in a restricted developmental stage by additional mutations.

The investigators also tested various treatments in mouse models of TCF3-HLF-positive ALL. They observed resistance to dasatinib, nucleotide analogs, mitotic spindle inhibitors, and polo-like and aurora kinase inhibitors.

On the other hand, the disease was sensitive to glucocorticoids, mTOR inhibitors, anthracyclines, bortezomib, the HSP90 inhibitor AUY922, and panobinostat.

The team also found evidence suggesting that BCL2 might promote leukemic cell survival and constitute a druggable target in TCF3-HLF-positive ALL. So they tested the BCL2 inhibitor venetoclax in the mice.

A 2-week course of daily venetoclax significantly delayed leukemia progression, and xenografts from relapsed patients and those with minimal residual disease remained sensitive to venetoclax. The drug also exhibited synergistic effects when combined with vincristine or dexamethasone.

“Further studies are now needed to test how the results of our study might be used for therapeutic possibilities,” Dr Bourquin concluded.

Colony of iPSCs

Image from the Salk Institute

Researchers say they have found a way to correct the chromosomal inversions that can cause severe hemophilia A.

The team used CRISPR-Cas9 RNA-guided engineered nucleases (RGENs) to correct the inversions and reverse factor VIII (FVIII) deficiency in patient-specific induced pluripotent stem cells (iPSCs).

Once the iPSCs had matured into endothelial cells, the group transplanted those cells into mice with hemophilia A.

This increased FVIII activity in the mice without any off-target effects.

The researchers described this work in Cell Stem Cell.

“We used CRISPR RGENs to repair two recurrent, large chromosomal inversions responsible for almost half of all severe hemophilia A cases,” said Jin-Soo Kim, PhD, of the Institute for Basic Science in Seoul, Korea.

The inversions involve the FVIII intron 1 homolog (responsible for about 5% of severe hemophilia A cases) and the intron 22 homolog (responsible for about 40% of cases).

The researchers first collected urinary cells from patients with these inversions, using the cells to generate iPSCs. The team then applied CRISPR-Cas9 RGENs.

The gene-editing technique effectively repaired the FVIII gene in iPSCs that had harbored either  inversion. The researchers then forced the corrected iPSCs to differentiate into mature endothelial cells and found these cells successfully expressed the FVIII protein.

To verify that the endothelial cells could reverse FVIII deficiency, the team transplanted the cells into mice with hemophilia A.

The mice soon began producing FVIII on their own, although the FVIII activity in these mice was 10% that of wild-type mice. The activity was higher than FVIII activity in control mice with hemophilia A (3.3% of wild-type mice), but the difference was not statistically significant.

“To the best of our knowledge, this report is the first demonstration that chromosomal inversions or other large rearrangements can be corrected using RGENs or any other programmable nuclease in patient iPSCs,” said Dong-Wook Kim, PhD, of Yonsei University College of Medicine in Seoul, Korea.

The researchers also noted that there was no evidence of off-target mutations with the 3 RGENS used in this study.

Colony of iPSCs

Image from the Salk Institute

Researchers say they have found a way to correct the chromosomal inversions that can cause severe hemophilia A.

The team used CRISPR-Cas9 RNA-guided engineered nucleases (RGENs) to correct the inversions and reverse factor VIII (FVIII) deficiency in patient-specific induced pluripotent stem cells (iPSCs).

Once the iPSCs had matured into endothelial cells, the group transplanted those cells into mice with hemophilia A.

This increased FVIII activity in the mice without any off-target effects.

The researchers described this work in Cell Stem Cell.

“We used CRISPR RGENs to repair two recurrent, large chromosomal inversions responsible for almost half of all severe hemophilia A cases,” said Jin-Soo Kim, PhD, of the Institute for Basic Science in Seoul, Korea.

The inversions involve the FVIII intron 1 homolog (responsible for about 5% of severe hemophilia A cases) and the intron 22 homolog (responsible for about 40% of cases).

The researchers first collected urinary cells from patients with these inversions, using the cells to generate iPSCs. The team then applied CRISPR-Cas9 RGENs.

The gene-editing technique effectively repaired the FVIII gene in iPSCs that had harbored either  inversion. The researchers then forced the corrected iPSCs to differentiate into mature endothelial cells and found these cells successfully expressed the FVIII protein.

To verify that the endothelial cells could reverse FVIII deficiency, the team transplanted the cells into mice with hemophilia A.

The mice soon began producing FVIII on their own, although the FVIII activity in these mice was 10% that of wild-type mice. The activity was higher than FVIII activity in control mice with hemophilia A (3.3% of wild-type mice), but the difference was not statistically significant.

“To the best of our knowledge, this report is the first demonstration that chromosomal inversions or other large rearrangements can be corrected using RGENs or any other programmable nuclease in patient iPSCs,” said Dong-Wook Kim, PhD, of Yonsei University College of Medicine in Seoul, Korea.

The researchers also noted that there was no evidence of off-target mutations with the 3 RGENS used in this study.

Colony of iPSCs

Image from the Salk Institute

Researchers say they have found a way to correct the chromosomal inversions that can cause severe hemophilia A.

The team used CRISPR-Cas9 RNA-guided engineered nucleases (RGENs) to correct the inversions and reverse factor VIII (FVIII) deficiency in patient-specific induced pluripotent stem cells (iPSCs).

Once the iPSCs had matured into endothelial cells, the group transplanted those cells into mice with hemophilia A.

This increased FVIII activity in the mice without any off-target effects.

The researchers described this work in Cell Stem Cell.

“We used CRISPR RGENs to repair two recurrent, large chromosomal inversions responsible for almost half of all severe hemophilia A cases,” said Jin-Soo Kim, PhD, of the Institute for Basic Science in Seoul, Korea.

The inversions involve the FVIII intron 1 homolog (responsible for about 5% of severe hemophilia A cases) and the intron 22 homolog (responsible for about 40% of cases).

The researchers first collected urinary cells from patients with these inversions, using the cells to generate iPSCs. The team then applied CRISPR-Cas9 RGENs.

The gene-editing technique effectively repaired the FVIII gene in iPSCs that had harbored either  inversion. The researchers then forced the corrected iPSCs to differentiate into mature endothelial cells and found these cells successfully expressed the FVIII protein.

To verify that the endothelial cells could reverse FVIII deficiency, the team transplanted the cells into mice with hemophilia A.

The mice soon began producing FVIII on their own, although the FVIII activity in these mice was 10% that of wild-type mice. The activity was higher than FVIII activity in control mice with hemophilia A (3.3% of wild-type mice), but the difference was not statistically significant.

“To the best of our knowledge, this report is the first demonstration that chromosomal inversions or other large rearrangements can be corrected using RGENs or any other programmable nuclease in patient iPSCs,” said Dong-Wook Kim, PhD, of Yonsei University College of Medicine in Seoul, Korea.

The researchers also noted that there was no evidence of off-target mutations with the 3 RGENS used in this study.

Drug production

Photo courtesy of the FDA

A new study indicates that drug manufacturers fail to report about 10% of serious and unexpected adverse events (AEs) within the timeframe set out in federal regulations.

Manufacturers are required to report a serious AE (death, hospitalization, disability, etc.) or unexpected AE (anything not listed in the drug’s label) to the US Food and Drug Administration (FDA) within 15 calendar days of learning about the event.

But an analysis of more than 1.6 million AE reports showed that manufacturers failed to meet this requirement for nearly 10% of AEs.

Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health in Minneapolis, and her colleagues conducted the analysis and detailed the results in JAMA Internal Medicine.

The team examined data from the FDA Adverse Event Reporting System for AE reports made from January 2004 through June 2014. The final study sample included only reports that were subject to the regulation requiring submission within 15 days—a total of 1,613,079 reports.

The researchers found that 9.94% of reports were not received by the FDA within the 15-day timeframe. This was a total of 160,383 reports—40,464 cases in which patients died and 119,919 in which they did not.

So 90.06% of reports (n=1,452,696) were reported within 15 days, 5.28% (n=85,161) were reported within 16 to 90 days, 2.19% (n=35,392) were reported within 91 to 180 days, and 2.47% (n=39,830) were reported after 180 days.

Multivariate analysis revealed that patient death was positively associated with delayed AE reporting. About 91% (90.71%) of AEs that did not involve death were reported within 15 days, compared to 88.25% of AEs that did involve death.

The percentage of reports received within 16 to 90 days was 5.19% for AEs without death and 6.42% for AEs with death. The percentage of reports received within 91 to 180 days was 1.98% and 2.53%, respectively. And the percentage of reports received after 180 days was 2.12% and 2.80%, respectively.

The researchers said perhaps manufacturers spend additional time verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.

In a related Editor’s Note, Rita F. Redberg, MD, editor of JAMA Internal Medicine, wrote that delays in reporting AEs should never occur because they mean exposing patients to serious harm, including death, that could potentially be avoided.

“One improvement would be for AE reports to go directly to the FDA instead of via the manufacturer . . . ,” she wrote. “Physicians and their patients must be knowledgeable of benefits, harms, and alternatives for a wide choice of treatments, especially those recently approved for which clinical experience is limited.”

Drug production

Photo courtesy of the FDA

A new study indicates that drug manufacturers fail to report about 10% of serious and unexpected adverse events (AEs) within the timeframe set out in federal regulations.

Manufacturers are required to report a serious AE (death, hospitalization, disability, etc.) or unexpected AE (anything not listed in the drug’s label) to the US Food and Drug Administration (FDA) within 15 calendar days of learning about the event.

But an analysis of more than 1.6 million AE reports showed that manufacturers failed to meet this requirement for nearly 10% of AEs.

Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health in Minneapolis, and her colleagues conducted the analysis and detailed the results in JAMA Internal Medicine.

The team examined data from the FDA Adverse Event Reporting System for AE reports made from January 2004 through June 2014. The final study sample included only reports that were subject to the regulation requiring submission within 15 days—a total of 1,613,079 reports.

The researchers found that 9.94% of reports were not received by the FDA within the 15-day timeframe. This was a total of 160,383 reports—40,464 cases in which patients died and 119,919 in which they did not.

So 90.06% of reports (n=1,452,696) were reported within 15 days, 5.28% (n=85,161) were reported within 16 to 90 days, 2.19% (n=35,392) were reported within 91 to 180 days, and 2.47% (n=39,830) were reported after 180 days.

Multivariate analysis revealed that patient death was positively associated with delayed AE reporting. About 91% (90.71%) of AEs that did not involve death were reported within 15 days, compared to 88.25% of AEs that did involve death.

The percentage of reports received within 16 to 90 days was 5.19% for AEs without death and 6.42% for AEs with death. The percentage of reports received within 91 to 180 days was 1.98% and 2.53%, respectively. And the percentage of reports received after 180 days was 2.12% and 2.80%, respectively.

The researchers said perhaps manufacturers spend additional time verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.

In a related Editor’s Note, Rita F. Redberg, MD, editor of JAMA Internal Medicine, wrote that delays in reporting AEs should never occur because they mean exposing patients to serious harm, including death, that could potentially be avoided.

“One improvement would be for AE reports to go directly to the FDA instead of via the manufacturer . . . ,” she wrote. “Physicians and their patients must be knowledgeable of benefits, harms, and alternatives for a wide choice of treatments, especially those recently approved for which clinical experience is limited.”

Drug production

Photo courtesy of the FDA

A new study indicates that drug manufacturers fail to report about 10% of serious and unexpected adverse events (AEs) within the timeframe set out in federal regulations.

Manufacturers are required to report a serious AE (death, hospitalization, disability, etc.) or unexpected AE (anything not listed in the drug’s label) to the US Food and Drug Administration (FDA) within 15 calendar days of learning about the event.

But an analysis of more than 1.6 million AE reports showed that manufacturers failed to meet this requirement for nearly 10% of AEs.

Pinar Karaca-Mandic, PhD, of the University of Minnesota School of Public Health in Minneapolis, and her colleagues conducted the analysis and detailed the results in JAMA Internal Medicine.

The team examined data from the FDA Adverse Event Reporting System for AE reports made from January 2004 through June 2014. The final study sample included only reports that were subject to the regulation requiring submission within 15 days—a total of 1,613,079 reports.

The researchers found that 9.94% of reports were not received by the FDA within the 15-day timeframe. This was a total of 160,383 reports—40,464 cases in which patients died and 119,919 in which they did not.

So 90.06% of reports (n=1,452,696) were reported within 15 days, 5.28% (n=85,161) were reported within 16 to 90 days, 2.19% (n=35,392) were reported within 91 to 180 days, and 2.47% (n=39,830) were reported after 180 days.

Multivariate analysis revealed that patient death was positively associated with delayed AE reporting. About 91% (90.71%) of AEs that did not involve death were reported within 15 days, compared to 88.25% of AEs that did involve death.

The percentage of reports received within 16 to 90 days was 5.19% for AEs without death and 6.42% for AEs with death. The percentage of reports received within 91 to 180 days was 1.98% and 2.53%, respectively. And the percentage of reports received after 180 days was 2.12% and 2.80%, respectively.

The researchers said perhaps manufacturers spend additional time verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime.

In a related Editor’s Note, Rita F. Redberg, MD, editor of JAMA Internal Medicine, wrote that delays in reporting AEs should never occur because they mean exposing patients to serious harm, including death, that could potentially be avoided.

“One improvement would be for AE reports to go directly to the FDA instead of via the manufacturer . . . ,” she wrote. “Physicians and their patients must be knowledgeable of benefits, harms, and alternatives for a wide choice of treatments, especially those recently approved for which clinical experience is limited.”

Cord blood for transplant

Photo courtesy of NHS

Investigators have reported favorable results of allogeneic hematopoietic stem cell transplant (HSCT) in a small study of patients with juvenile myelomonocytic leukemia (JMML).

The team said the positive outcomes may be a result of conditioning with busulfan and melphalan (BuMel) or the conventional-dose chemotherapy some patients received before HSCT.

Regardless, all 7 patients studied are in remission at more than 1 year of follow-up.

“The lack of transplant-related mortality in the group of children we studied . . . suggests that BuMel may represent a successful HSCT high-dose chemotherapy regimen,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“It is also possible that administering conventional-dose chemotherapy before HSCT to patients with more progressive disease may have contributed to the improved outcomes.”

Dr Abdel-Azim and his colleagues described this research in a letter to Blood.

Conventional chemo and transplant

The investigators retrospectively analyzed 7 JMML patients with a median age of 2.6 years at HSCT.

Five patients received conventional-dose chemotherapy before transplant. All of these patients received mercaptopurine. One received hydroxyurea as well, and another patient received fludarabine, cytarabine, and cis-retinoic acid.

As for transplant, 2 patients received a 10/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched unrelated bone marrow graft, and 3 patients received cord blood grafts.

The median total nucleated cell count was 4.2 × 10⁸ cells/kg, and the median CD34 cell dose was 3.3 × 10⁶ cells/kg.

Conditioning and GVHD prophylaxis

All 7 patients received backbone conditioning with BuMel: Bu at 1 mg/kg dose every 6 hours intravenously on days −8 to −5 (with therapeutic drug monitoring to achieve overall concentration steady state [CSS] of 800-1000 ng/mL) and Mel at 45 mg/m² per day intravenously on days −4 to −2.

The median Bu CSS and area under the curve were 884 µg/L (range, 560-1096) and 1293 µmol/L-minute (range, 819-1601), respectively.

The patient with a 9/10 HLA-matched related graft received BuMel and fludarabine at 35 mg/m² per day intravenously on days −7 to −4.

The patient with the 9/10 HLA-matched unrelated graft received BuMel and alemtuzumab at 12 mg/m² intravenously on day −10 and 20 mg/m² on day −9, with methylprednisolone at 2 mg/kg per day in divided doses during the alemtuzumab infusion.

The patients who received cord blood grafts received BuMel and rabbit antithymocyte globulin at 2.5 mg/kg per day intravenously on days −4 to −1. They also received methylprednisolone at 2 mg/kg per day in divided doses during antithymocyte globulin infusion, then tapered over 6 weeks.

All patients received tacrolimus as graft-vs-host disease (GVHD) prophylaxis. Patients who received bone marrow grafts also received methotrexate at 5 mg/m² on days 3, 6, and 11.

Outcomes

The median time to neutrophil engraftment (≥500/mm³) was 20 days, and the median time to platelet engraftment (≥20 000/mm³) was 36 days.

Six patients (85.7%) achieved predominant (>95%) donor hematopoietic stem cell engraftment.

One patient who received a cord blood graft had autologous recovery at day 54. She went on to receive a related haploidentical HSCT on day 105. One hundred days later, she is in remission, with predominant donor chimerism.

The patient who received the 9/10 HLA-matched related graft developed grade 4 acute GVHD, followed by severe chronic GVHD that required bowel resection.

This patient and one of the patients who received a 10/10 HLA-matched related graft developed severe sinusoidal obstructive syndrome, which resolved with supportive care.

At a median follow-up of 25.3 months (range, 6-99.3), all 7 patients are in remission.

The investigators said their target Bu CSS may have contributed to the improved outcomes they observed, or pre-HSCT chemotherapy may have been a contributing factor. A prospective clinical trial could provide answers.

Cord blood for transplant

Photo courtesy of NHS

Investigators have reported favorable results of allogeneic hematopoietic stem cell transplant (HSCT) in a small study of patients with juvenile myelomonocytic leukemia (JMML).

The team said the positive outcomes may be a result of conditioning with busulfan and melphalan (BuMel) or the conventional-dose chemotherapy some patients received before HSCT.

Regardless, all 7 patients studied are in remission at more than 1 year of follow-up.

“The lack of transplant-related mortality in the group of children we studied . . . suggests that BuMel may represent a successful HSCT high-dose chemotherapy regimen,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“It is also possible that administering conventional-dose chemotherapy before HSCT to patients with more progressive disease may have contributed to the improved outcomes.”

Dr Abdel-Azim and his colleagues described this research in a letter to Blood.

Conventional chemo and transplant

The investigators retrospectively analyzed 7 JMML patients with a median age of 2.6 years at HSCT.

Five patients received conventional-dose chemotherapy before transplant. All of these patients received mercaptopurine. One received hydroxyurea as well, and another patient received fludarabine, cytarabine, and cis-retinoic acid.

As for transplant, 2 patients received a 10/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched unrelated bone marrow graft, and 3 patients received cord blood grafts.

The median total nucleated cell count was 4.2 × 10⁸ cells/kg, and the median CD34 cell dose was 3.3 × 10⁶ cells/kg.

Conditioning and GVHD prophylaxis

All 7 patients received backbone conditioning with BuMel: Bu at 1 mg/kg dose every 6 hours intravenously on days −8 to −5 (with therapeutic drug monitoring to achieve overall concentration steady state [CSS] of 800-1000 ng/mL) and Mel at 45 mg/m² per day intravenously on days −4 to −2.

The median Bu CSS and area under the curve were 884 µg/L (range, 560-1096) and 1293 µmol/L-minute (range, 819-1601), respectively.

The patient with a 9/10 HLA-matched related graft received BuMel and fludarabine at 35 mg/m² per day intravenously on days −7 to −4.

The patient with the 9/10 HLA-matched unrelated graft received BuMel and alemtuzumab at 12 mg/m² intravenously on day −10 and 20 mg/m² on day −9, with methylprednisolone at 2 mg/kg per day in divided doses during the alemtuzumab infusion.

The patients who received cord blood grafts received BuMel and rabbit antithymocyte globulin at 2.5 mg/kg per day intravenously on days −4 to −1. They also received methylprednisolone at 2 mg/kg per day in divided doses during antithymocyte globulin infusion, then tapered over 6 weeks.

All patients received tacrolimus as graft-vs-host disease (GVHD) prophylaxis. Patients who received bone marrow grafts also received methotrexate at 5 mg/m² on days 3, 6, and 11.

Outcomes

The median time to neutrophil engraftment (≥500/mm³) was 20 days, and the median time to platelet engraftment (≥20 000/mm³) was 36 days.

Six patients (85.7%) achieved predominant (>95%) donor hematopoietic stem cell engraftment.

One patient who received a cord blood graft had autologous recovery at day 54. She went on to receive a related haploidentical HSCT on day 105. One hundred days later, she is in remission, with predominant donor chimerism.

The patient who received the 9/10 HLA-matched related graft developed grade 4 acute GVHD, followed by severe chronic GVHD that required bowel resection.

This patient and one of the patients who received a 10/10 HLA-matched related graft developed severe sinusoidal obstructive syndrome, which resolved with supportive care.

At a median follow-up of 25.3 months (range, 6-99.3), all 7 patients are in remission.

The investigators said their target Bu CSS may have contributed to the improved outcomes they observed, or pre-HSCT chemotherapy may have been a contributing factor. A prospective clinical trial could provide answers.

Cord blood for transplant

Photo courtesy of NHS

Investigators have reported favorable results of allogeneic hematopoietic stem cell transplant (HSCT) in a small study of patients with juvenile myelomonocytic leukemia (JMML).

The team said the positive outcomes may be a result of conditioning with busulfan and melphalan (BuMel) or the conventional-dose chemotherapy some patients received before HSCT.

Regardless, all 7 patients studied are in remission at more than 1 year of follow-up.

“The lack of transplant-related mortality in the group of children we studied . . . suggests that BuMel may represent a successful HSCT high-dose chemotherapy regimen,” said study author Hisham Abdel-Azim, MD, of Children’s Hospital Los Angeles in California.

“It is also possible that administering conventional-dose chemotherapy before HSCT to patients with more progressive disease may have contributed to the improved outcomes.”

Dr Abdel-Azim and his colleagues described this research in a letter to Blood.

Conventional chemo and transplant

The investigators retrospectively analyzed 7 JMML patients with a median age of 2.6 years at HSCT.

Five patients received conventional-dose chemotherapy before transplant. All of these patients received mercaptopurine. One received hydroxyurea as well, and another patient received fludarabine, cytarabine, and cis-retinoic acid.

As for transplant, 2 patients received a 10/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched related bone marrow graft, 1 received a 9/10 HLA-matched unrelated bone marrow graft, and 3 patients received cord blood grafts.

The median total nucleated cell count was 4.2 × 10⁸ cells/kg, and the median CD34 cell dose was 3.3 × 10⁶ cells/kg.

Conditioning and GVHD prophylaxis

All 7 patients received backbone conditioning with BuMel: Bu at 1 mg/kg dose every 6 hours intravenously on days −8 to −5 (with therapeutic drug monitoring to achieve overall concentration steady state [CSS] of 800-1000 ng/mL) and Mel at 45 mg/m² per day intravenously on days −4 to −2.

The median Bu CSS and area under the curve were 884 µg/L (range, 560-1096) and 1293 µmol/L-minute (range, 819-1601), respectively.

The patient with a 9/10 HLA-matched related graft received BuMel and fludarabine at 35 mg/m² per day intravenously on days −7 to −4.

The patient with the 9/10 HLA-matched unrelated graft received BuMel and alemtuzumab at 12 mg/m² intravenously on day −10 and 20 mg/m² on day −9, with methylprednisolone at 2 mg/kg per day in divided doses during the alemtuzumab infusion.

The patients who received cord blood grafts received BuMel and rabbit antithymocyte globulin at 2.5 mg/kg per day intravenously on days −4 to −1. They also received methylprednisolone at 2 mg/kg per day in divided doses during antithymocyte globulin infusion, then tapered over 6 weeks.

All patients received tacrolimus as graft-vs-host disease (GVHD) prophylaxis. Patients who received bone marrow grafts also received methotrexate at 5 mg/m² on days 3, 6, and 11.

Outcomes

The median time to neutrophil engraftment (≥500/mm³) was 20 days, and the median time to platelet engraftment (≥20 000/mm³) was 36 days.

Six patients (85.7%) achieved predominant (>95%) donor hematopoietic stem cell engraftment.

One patient who received a cord blood graft had autologous recovery at day 54. She went on to receive a related haploidentical HSCT on day 105. One hundred days later, she is in remission, with predominant donor chimerism.

The patient who received the 9/10 HLA-matched related graft developed grade 4 acute GVHD, followed by severe chronic GVHD that required bowel resection.

This patient and one of the patients who received a 10/10 HLA-matched related graft developed severe sinusoidal obstructive syndrome, which resolved with supportive care.

At a median follow-up of 25.3 months (range, 6-99.3), all 7 patients are in remission.

The investigators said their target Bu CSS may have contributed to the improved outcomes they observed, or pre-HSCT chemotherapy may have been a contributing factor. A prospective clinical trial could provide answers.

NEW YORK (Reuters Health) - The "vast majority" of elderly patients admitted with small bowel obstruction (SBO) are hospitalized for more than two days, and the diagnosis alone should allow appropriate Medicare coverage, according to a new study.

In a paper online July 1 in Annals of Surgery, Dr. Zara Cooper, of Brigham and Women's Hospital, Boston, and colleagues noted that their study was prompted by the Two-Midnight Rule established by the Centers for Medicare & Medicaid Services (CMS) in 2013.

The authors explained that if a physician expects a patient to need a hospital stay that crosses two midnights and thus admits the patient, related costs may be covered. However, shorter stays are deemed as observational and can raise the possibility of non-reimbursement for hospitals.

For example, if someone is admitted as an inpatient, but discharged in less than two days, payment will be made only if it can be documented that a longer stay was reasonably expected and unforeseen circumstances led to the shorter stay. Hospital stays that are incorrectly classified or have improperly documented changes in admission status will not be paid.

However, Dr. Cooper told Reuters Health by email, "Older patients with SBO, a very common diagnosis, should be presumed to be admitted for more than two midnights and hospitals should not get penalized."

She and her colleagues pointed out that SBO accounts for about 15% of surgical admissions to U.S. hospitals and more than $1 billion in annual hospital charges. However, diagnosis requires surgeons to observe patients to determine if surgery is warranted.

Thus, the authors wrote, "It is critically important for surgeons to correctly assign admission status for patients with SBO to ensure that hospitals are reimbursed appropriately, and patients are not unduly burdened."

The investigators examined data on 855 older patients admitted with SBO from 2006 and 2013. Of these, 816 (95%) stayed for two midnights or longer. This was true of all patients aged 85 years or older (n=108, approximately 13%).

The only significant difference in clinical characteristics was the presence of inflammatory bowel disease. Of five such patients, only one stayed for less than two midnights.

"Based on our study and others," the investigators wrote, "we propose that hospital admission for SBO in elderly patients is sufficient justification for the reasonable expectation" of the required length of stay for reimbursement.

This also may be true of other conditions. Dr. Cooper concluded, "More studies like this are needed in surgical patients to better understand the impact of CMS admission guidelines. The rule may not make sense in certain populations, leading to heavy and unfair penalties for hospitals."

The authors reported no disclosures.

NEW YORK (Reuters Health) - The "vast majority" of elderly patients admitted with small bowel obstruction (SBO) are hospitalized for more than two days, and the diagnosis alone should allow appropriate Medicare coverage, according to a new study.

In a paper online July 1 in Annals of Surgery, Dr. Zara Cooper, of Brigham and Women's Hospital, Boston, and colleagues noted that their study was prompted by the Two-Midnight Rule established by the Centers for Medicare & Medicaid Services (CMS) in 2013.

The authors explained that if a physician expects a patient to need a hospital stay that crosses two midnights and thus admits the patient, related costs may be covered. However, shorter stays are deemed as observational and can raise the possibility of non-reimbursement for hospitals.

For example, if someone is admitted as an inpatient, but discharged in less than two days, payment will be made only if it can be documented that a longer stay was reasonably expected and unforeseen circumstances led to the shorter stay. Hospital stays that are incorrectly classified or have improperly documented changes in admission status will not be paid.

However, Dr. Cooper told Reuters Health by email, "Older patients with SBO, a very common diagnosis, should be presumed to be admitted for more than two midnights and hospitals should not get penalized."

She and her colleagues pointed out that SBO accounts for about 15% of surgical admissions to U.S. hospitals and more than $1 billion in annual hospital charges. However, diagnosis requires surgeons to observe patients to determine if surgery is warranted.

Thus, the authors wrote, "It is critically important for surgeons to correctly assign admission status for patients with SBO to ensure that hospitals are reimbursed appropriately, and patients are not unduly burdened."

The investigators examined data on 855 older patients admitted with SBO from 2006 and 2013. Of these, 816 (95%) stayed for two midnights or longer. This was true of all patients aged 85 years or older (n=108, approximately 13%).

The only significant difference in clinical characteristics was the presence of inflammatory bowel disease. Of five such patients, only one stayed for less than two midnights.

"Based on our study and others," the investigators wrote, "we propose that hospital admission for SBO in elderly patients is sufficient justification for the reasonable expectation" of the required length of stay for reimbursement.

This also may be true of other conditions. Dr. Cooper concluded, "More studies like this are needed in surgical patients to better understand the impact of CMS admission guidelines. The rule may not make sense in certain populations, leading to heavy and unfair penalties for hospitals."

The authors reported no disclosures.

NEW YORK (Reuters Health) - The "vast majority" of elderly patients admitted with small bowel obstruction (SBO) are hospitalized for more than two days, and the diagnosis alone should allow appropriate Medicare coverage, according to a new study.

In a paper online July 1 in Annals of Surgery, Dr. Zara Cooper, of Brigham and Women's Hospital, Boston, and colleagues noted that their study was prompted by the Two-Midnight Rule established by the Centers for Medicare & Medicaid Services (CMS) in 2013.

The authors explained that if a physician expects a patient to need a hospital stay that crosses two midnights and thus admits the patient, related costs may be covered. However, shorter stays are deemed as observational and can raise the possibility of non-reimbursement for hospitals.

For example, if someone is admitted as an inpatient, but discharged in less than two days, payment will be made only if it can be documented that a longer stay was reasonably expected and unforeseen circumstances led to the shorter stay. Hospital stays that are incorrectly classified or have improperly documented changes in admission status will not be paid.

However, Dr. Cooper told Reuters Health by email, "Older patients with SBO, a very common diagnosis, should be presumed to be admitted for more than two midnights and hospitals should not get penalized."

She and her colleagues pointed out that SBO accounts for about 15% of surgical admissions to U.S. hospitals and more than $1 billion in annual hospital charges. However, diagnosis requires surgeons to observe patients to determine if surgery is warranted.

Thus, the authors wrote, "It is critically important for surgeons to correctly assign admission status for patients with SBO to ensure that hospitals are reimbursed appropriately, and patients are not unduly burdened."

The investigators examined data on 855 older patients admitted with SBO from 2006 and 2013. Of these, 816 (95%) stayed for two midnights or longer. This was true of all patients aged 85 years or older (n=108, approximately 13%).

The only significant difference in clinical characteristics was the presence of inflammatory bowel disease. Of five such patients, only one stayed for less than two midnights.

"Based on our study and others," the investigators wrote, "we propose that hospital admission for SBO in elderly patients is sufficient justification for the reasonable expectation" of the required length of stay for reimbursement.

This also may be true of other conditions. Dr. Cooper concluded, "More studies like this are needed in surgical patients to better understand the impact of CMS admission guidelines. The rule may not make sense in certain populations, leading to heavy and unfair penalties for hospitals."

The authors reported no disclosures.

NEW YORK (Reuters Health) - In certain circumstances one widely used test for vitamin D intoxication, the Diasorin radioimmunoassay, may not be entirely reliable, according to two case studies by U.S. and Irish investigators.

"Our study," Dr. Michael A. Levine told Reuters Health by email, "highlights the continuing challenge that we face when using current assay technologies to measure vitamin D metabolites." The patients involved "developed vitamin D toxicity from inadvertent overdosage using standard over-the-counter preparations of vitamin D."

In a June 22 online paper in the Journal of Clinical Endocrinology & Metabolism, Dr. Levine, of the University of Pennsylvania, Philadelphia, and colleagues note that vitamin D intoxication is characterized by elevated serum 25-hydroxyvitamin D (25(OH)D) and suppressed serum 1,25-dihydroxvitamin D (1,25(OH)2D).

The team used both the Diasorin radioimmunaossay test (RIA) and liquid chromatography and tandem mass spectrometry (LC-MS/MS) to evaluate samples from two retrospectively identified patients with hypercalcemia. One was a 15-year-old male with a two-week history of postprandial vomiting, abdominal pain and polyuria. The other, a 17-year old female, had a history of weight loss.

Both had elevated serum 1,25(OH)2D by RIA, but normal serum 1,25(OH)2D concentrations by LC-MS/MS. To help explain these surprising findings the team conducted further in vitro experiments on serum samples from a random set of inpatients and outpatients.

The team noted that concentrations of 25(OH)D2 or 25(OH)D3 increased as expected based on the amount of vitamin D metabolite added to pooled serum samples or artificial serum matrix in all experiments.

The addition of 100 ng/mL of 25(OH)D3 to pooled patient serum resulted in a median increase of 114% in measured 1,25(OH)D2 via RIA and a 21% increase via LC-MS/MS. At 700 ng/mL, the increase was 349% with RIA and 117% with LC-MS/MS.

Thus, wrote the researchers, "We recommend measurement of serum 24,25(OH)2D and use of LC-MS/MS, which appears less susceptible to this interference, to reassess serum levels of 1,25(OH)2D when the clinical scenario is confusing."

Summing up, Dr. Levine said, "Assessment of plasma levels of the most active vitamin D metabolite, 1,25(OH)2D, using a common laboratory immunoassay pointed away from nutritional vitamin D intoxication and suggested other more worrisome diagnoses. Repeating the testing with a mass spectrometer assay confirmed the clinical diagnosis of vitamin D intoxication."

He concluded, "Clinicians must remember that laboratory tests are not 100% reliable, and they must continue to rely upon their clinical judgment when confronted with test results that do not make sense."

Diasorin did not respond to a request for comment.

The authors reported no financial disclosures or competing interests.

NEW YORK (Reuters Health) - In certain circumstances one widely used test for vitamin D intoxication, the Diasorin radioimmunoassay, may not be entirely reliable, according to two case studies by U.S. and Irish investigators.

"Our study," Dr. Michael A. Levine told Reuters Health by email, "highlights the continuing challenge that we face when using current assay technologies to measure vitamin D metabolites." The patients involved "developed vitamin D toxicity from inadvertent overdosage using standard over-the-counter preparations of vitamin D."

In a June 22 online paper in the Journal of Clinical Endocrinology & Metabolism, Dr. Levine, of the University of Pennsylvania, Philadelphia, and colleagues note that vitamin D intoxication is characterized by elevated serum 25-hydroxyvitamin D (25(OH)D) and suppressed serum 1,25-dihydroxvitamin D (1,25(OH)2D).

The team used both the Diasorin radioimmunaossay test (RIA) and liquid chromatography and tandem mass spectrometry (LC-MS/MS) to evaluate samples from two retrospectively identified patients with hypercalcemia. One was a 15-year-old male with a two-week history of postprandial vomiting, abdominal pain and polyuria. The other, a 17-year old female, had a history of weight loss.

Both had elevated serum 1,25(OH)2D by RIA, but normal serum 1,25(OH)2D concentrations by LC-MS/MS. To help explain these surprising findings the team conducted further in vitro experiments on serum samples from a random set of inpatients and outpatients.

The team noted that concentrations of 25(OH)D2 or 25(OH)D3 increased as expected based on the amount of vitamin D metabolite added to pooled serum samples or artificial serum matrix in all experiments.

The addition of 100 ng/mL of 25(OH)D3 to pooled patient serum resulted in a median increase of 114% in measured 1,25(OH)D2 via RIA and a 21% increase via LC-MS/MS. At 700 ng/mL, the increase was 349% with RIA and 117% with LC-MS/MS.

Thus, wrote the researchers, "We recommend measurement of serum 24,25(OH)2D and use of LC-MS/MS, which appears less susceptible to this interference, to reassess serum levels of 1,25(OH)2D when the clinical scenario is confusing."

Summing up, Dr. Levine said, "Assessment of plasma levels of the most active vitamin D metabolite, 1,25(OH)2D, using a common laboratory immunoassay pointed away from nutritional vitamin D intoxication and suggested other more worrisome diagnoses. Repeating the testing with a mass spectrometer assay confirmed the clinical diagnosis of vitamin D intoxication."

He concluded, "Clinicians must remember that laboratory tests are not 100% reliable, and they must continue to rely upon their clinical judgment when confronted with test results that do not make sense."

Diasorin did not respond to a request for comment.

The authors reported no financial disclosures or competing interests.

NEW YORK (Reuters Health) - In certain circumstances one widely used test for vitamin D intoxication, the Diasorin radioimmunoassay, may not be entirely reliable, according to two case studies by U.S. and Irish investigators.

"Our study," Dr. Michael A. Levine told Reuters Health by email, "highlights the continuing challenge that we face when using current assay technologies to measure vitamin D metabolites." The patients involved "developed vitamin D toxicity from inadvertent overdosage using standard over-the-counter preparations of vitamin D."

In a June 22 online paper in the Journal of Clinical Endocrinology & Metabolism, Dr. Levine, of the University of Pennsylvania, Philadelphia, and colleagues note that vitamin D intoxication is characterized by elevated serum 25-hydroxyvitamin D (25(OH)D) and suppressed serum 1,25-dihydroxvitamin D (1,25(OH)2D).

The team used both the Diasorin radioimmunaossay test (RIA) and liquid chromatography and tandem mass spectrometry (LC-MS/MS) to evaluate samples from two retrospectively identified patients with hypercalcemia. One was a 15-year-old male with a two-week history of postprandial vomiting, abdominal pain and polyuria. The other, a 17-year old female, had a history of weight loss.

Both had elevated serum 1,25(OH)2D by RIA, but normal serum 1,25(OH)2D concentrations by LC-MS/MS. To help explain these surprising findings the team conducted further in vitro experiments on serum samples from a random set of inpatients and outpatients.

The team noted that concentrations of 25(OH)D2 or 25(OH)D3 increased as expected based on the amount of vitamin D metabolite added to pooled serum samples or artificial serum matrix in all experiments.

The addition of 100 ng/mL of 25(OH)D3 to pooled patient serum resulted in a median increase of 114% in measured 1,25(OH)D2 via RIA and a 21% increase via LC-MS/MS. At 700 ng/mL, the increase was 349% with RIA and 117% with LC-MS/MS.

Thus, wrote the researchers, "We recommend measurement of serum 24,25(OH)2D and use of LC-MS/MS, which appears less susceptible to this interference, to reassess serum levels of 1,25(OH)2D when the clinical scenario is confusing."

Summing up, Dr. Levine said, "Assessment of plasma levels of the most active vitamin D metabolite, 1,25(OH)2D, using a common laboratory immunoassay pointed away from nutritional vitamin D intoxication and suggested other more worrisome diagnoses. Repeating the testing with a mass spectrometer assay confirmed the clinical diagnosis of vitamin D intoxication."

He concluded, "Clinicians must remember that laboratory tests are not 100% reliable, and they must continue to rely upon their clinical judgment when confronted with test results that do not make sense."

Diasorin did not respond to a request for comment.

The authors reported no financial disclosures or competing interests.