HT Staff

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Researcher in the lab

Credit: Rhoda Baer

Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.

Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.

And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.

“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.

To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.

As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.

Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.

In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.

The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.

Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.

When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.

The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

Credit: National Institute

of General Medical Sciences

There are significant challenges to overcome before whole-genome sequencing can be routinely used in the clinic, researchers have reported in JAMA.

In sequencing the entire genome of 12 healthy individuals, the team found they sometimes had difficulty identifying

variants in disease-associated genes, disagreed about which variants were particularly important for disease, and were uncertain about clinically reportable findings.

The research also revealed that detailed genome analysis required up to 100 hours of manual assessment per person, and the total cost of this process (including follow-up tests) could exceed $15,000 per person.

This is more expensive and labor-intensive than previous estimates, the researchers noted.

“We need to be very honest about what we can and cannot do at this point in time,” said study author Euan Ashley, MB ChB, DPhil, of Stanford University in California.

“Our hope is that the identification of specific hurdles will allow researchers in this field to focus their efforts on overcoming them to make this technique clinically useful.”

To identify these hurdles, Dr Ashley and his colleagues evaluated whole-genome sequencing in 12 healthy individuals. The team took note of the degree of sequencing accuracy necessary to make clinical decisions, the time it took to manually analyze each person’s results, and the costs involved.

The researchers discovered that sequencing could not provide reliable results regarding all inherited disease genes or consistently detect variants with the highest potential clinical effects.

Depending on the sequencing platform used, 10% to 19% of inherited disease genes were not covered to accepted standards for single-nucleotide variant discovery.

And although genotype concordance was high for previously described single-nucleotide variants—99% to 100%—it was low for small insertions and deletions—53% to 59%.

“It’s ironic, and slightly sobering, that we struggle the most in identifying insertions and deletions—those changes in the genome that are most impactful,” Dr Ashley said.

Nevertheless, he and his colleagues were able to identify an average of about 100 variants per person that were considered important enough for follow-up. Each variant required about an hour of investigation to assess the relevant scientific literature and determine whether the change was likely to modify disease risk in the individual.

After this process, the researchers were left with approximately 2 to 6 results they felt could be clinically important.

The variants expected to have potential health consequences were shared with 3 primary care physicians and 2 medical geneticists, who independently studied the results and recommended possible follow-up tests for each person.

The researchers estimated that the median cost for sequencing and variant interpretation was $14,815 (range, $14,050 to $15,715), plus the costs of computing infrastructure and data storage. And the projected costs for follow-up tests ranged from $351 to $776.

Despite the challenges they identified, the team said they are confident that whole-genome sequencing is worth pursuing.

“Our intention in doing this analysis was to draw a line describing where we are with this technology at this point in time and identify how best to move forward,” Dr Ashley said. “Things are becoming more clear, and the challenges to bringing this technique to the clinic are becoming crystallized.”

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

Worker prepares capsules

for use in a clinical trial

Credit: Esther Dyson

Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.

Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.

Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.

And discontinued trials were significantly more likely than completed trials to remain unpublished.

The most common reason for discontinuation was insufficient subject enrollment.

Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.

Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.

Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).

The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).

A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.

Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.

They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.

Science journals

Credit: CDC/James Gathany

New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.

During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.

This included differences in study group data, intervention information, and primary and secondary endpoints.

Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.

The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).

Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.

Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.

For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.

Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.

There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.

The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.

These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.

Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.

The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.

Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.

Science journals

Credit: CDC/James Gathany

New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.

During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.

This included differences in study group data, intervention information, and primary and secondary endpoints.

Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.

The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).

Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.

Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.

For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.

Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.

There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.

The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.

These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.

Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.

The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.

Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.

Science journals

Credit: CDC/James Gathany

New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.

During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.

This included differences in study group data, intervention information, and primary and secondary endpoints.

Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.

The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).

Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.

Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.

For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.

Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.

There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.

The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.

These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.

Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.

The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.

Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.

Blood samples

Credit: Graham Colm

Investigators have found they can use DNA methylation to simultaneously count multiple leukocyte subsets in blood samples, and they’ve reported this finding in Genome Biology.

The researchers noted that current methods of counting leukocytes in a blood sample require whole cells.

But as their newly developed method relies on DNA, it can be useful even in archived blood samples in which cells have lost their physical integrity.

“Once you understand the unique and really immutable [methylation] signature that directs the differentiation of the cell, then you can use that, and you don’t need the cell anymore,” said study author Karl Kelsey, MD, of Brown University in Providence, Rhode Island.

So the new test detects those methylation signatures in a blood sample and, with the help of algorithms, allows researchers to count how many cells of each type are in the sample.

Dr Kelsey and his colleagues found they could quantify T cells, B cells, NK cells, monocytes, eosinophils, basophils, and neutrophils.

The investigators tested their method using fresh blood samples from more than 80 donors.

The new technique proved as accurate as 3 gold-standard methods of cell quantification: manual 5-part differential, complete blood count with automated 5-part differential, and fluorescence activated cell sorting.

In further experiments, the team found their technique could detect the mixtures of immune cells associated with known diseases.

The method also proved effective with blood exposed to storage conditions, such as freezing and the addition of anticoagulants.

Moreover, the researchers showed that to distinguish among and count those various immune cell types, they only needed to measure a few dozen methylation marks in the DNA. In other words, what’s sufficient to constitute a signature can be quite short.

This method has proven feasible enough that other epidemiology research labs are already using it, Dr Kelsey said. And Brown University has applied for a patent on the technique.

Dr Kelsey said the method has the potential to be cheaper and faster than current techniques, although the investigators didn’t test that in their experiments.

Blood samples

Credit: Graham Colm

Investigators have found they can use DNA methylation to simultaneously count multiple leukocyte subsets in blood samples, and they’ve reported this finding in Genome Biology.

The researchers noted that current methods of counting leukocytes in a blood sample require whole cells.

But as their newly developed method relies on DNA, it can be useful even in archived blood samples in which cells have lost their physical integrity.

“Once you understand the unique and really immutable [methylation] signature that directs the differentiation of the cell, then you can use that, and you don’t need the cell anymore,” said study author Karl Kelsey, MD, of Brown University in Providence, Rhode Island.

So the new test detects those methylation signatures in a blood sample and, with the help of algorithms, allows researchers to count how many cells of each type are in the sample.

Dr Kelsey and his colleagues found they could quantify T cells, B cells, NK cells, monocytes, eosinophils, basophils, and neutrophils.

The investigators tested their method using fresh blood samples from more than 80 donors.

The new technique proved as accurate as 3 gold-standard methods of cell quantification: manual 5-part differential, complete blood count with automated 5-part differential, and fluorescence activated cell sorting.

In further experiments, the team found their technique could detect the mixtures of immune cells associated with known diseases.

The method also proved effective with blood exposed to storage conditions, such as freezing and the addition of anticoagulants.

Moreover, the researchers showed that to distinguish among and count those various immune cell types, they only needed to measure a few dozen methylation marks in the DNA. In other words, what’s sufficient to constitute a signature can be quite short.

This method has proven feasible enough that other epidemiology research labs are already using it, Dr Kelsey said. And Brown University has applied for a patent on the technique.

Dr Kelsey said the method has the potential to be cheaper and faster than current techniques, although the investigators didn’t test that in their experiments.

Blood samples

Credit: Graham Colm

Investigators have found they can use DNA methylation to simultaneously count multiple leukocyte subsets in blood samples, and they’ve reported this finding in Genome Biology.

The researchers noted that current methods of counting leukocytes in a blood sample require whole cells.

But as their newly developed method relies on DNA, it can be useful even in archived blood samples in which cells have lost their physical integrity.

“Once you understand the unique and really immutable [methylation] signature that directs the differentiation of the cell, then you can use that, and you don’t need the cell anymore,” said study author Karl Kelsey, MD, of Brown University in Providence, Rhode Island.

So the new test detects those methylation signatures in a blood sample and, with the help of algorithms, allows researchers to count how many cells of each type are in the sample.

Dr Kelsey and his colleagues found they could quantify T cells, B cells, NK cells, monocytes, eosinophils, basophils, and neutrophils.

The investigators tested their method using fresh blood samples from more than 80 donors.

The new technique proved as accurate as 3 gold-standard methods of cell quantification: manual 5-part differential, complete blood count with automated 5-part differential, and fluorescence activated cell sorting.

In further experiments, the team found their technique could detect the mixtures of immune cells associated with known diseases.

The method also proved effective with blood exposed to storage conditions, such as freezing and the addition of anticoagulants.

Moreover, the researchers showed that to distinguish among and count those various immune cell types, they only needed to measure a few dozen methylation marks in the DNA. In other words, what’s sufficient to constitute a signature can be quite short.

This method has proven feasible enough that other epidemiology research labs are already using it, Dr Kelsey said. And Brown University has applied for a patent on the technique.

Dr Kelsey said the method has the potential to be cheaper and faster than current techniques, although the investigators didn’t test that in their experiments.

 

 

Pill production

Credit: FDA

 

Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.

The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).

The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.

“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.

Solid survival rates in CLL

The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).

They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.

In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.

Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.

Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).

The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.

The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.

Longer response duration in iNHL

The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).

Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).

The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.

The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.

Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).

The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.

Short response, survival duration in MCL

The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.

Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.

The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.

Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).

The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.

Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.

“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”

 

 

Pill production

Credit: FDA

 

Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.

The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).

The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.

“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.

Solid survival rates in CLL

The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).

They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.

In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.

Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.

Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).

The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.

The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.

Longer response duration in iNHL

The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).

Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).

The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.

The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.

Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).

The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.

Short response, survival duration in MCL

The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.

Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.

The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.

Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).

The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.

Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.

“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”

 

 

Pill production

Credit: FDA

 

Results of a phase 1 study suggest the PI3K delta inhibitor idelalisib can produce durable responses in certain patients with relapsed or refractory disease.

The drug elicited a response rate of 72% in patients with chronic lymphocytic leukemia (CLL), 47% in indolent non-Hodgkin lymphoma (iNHL), and 40% in mantle cell lymphoma(MCL).

The median duration of response was 16.2 months among CLL patients, 18.4 months among iNHL patients, and 2.7 months among those with MCL.

“Considering the high number of previous therapies that these patients had received, higher than we sometimes see in comparable studies, the efficacy of idelalisib that we observed was remarkable,” said study author Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

In 3 papers published in Blood, Dr Flinn and his colleagues presented data from this phase 1 study of idelalisib. After an initial study involving all trial participants, the patients were separated into CLL, iNHL, and MCL disease cohorts.

Solid survival rates in CLL

The researchers evaluated idelalisib in 54 patients with relapsed or refractory CLL. The patients had received a median of 5 prior treatments (range, 2-14).

They had a median age of 63 years (range 37-82), 80% had bulky lymphadenopathy, 70% had treatment-refractory disease, 91% had unmutated IGHV, and 24% had del17p and/or TP53 mutation.

In the primary study, the patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for 48 weeks. If they continued to derive clinical benefit, patients could continue treatment on an extension study.

Fifty-four percent of patients discontinued treatment during the primary study period. Twenty-eight percent stopped because of disease progression, 9% due to adverse events (AEs), and 6% due to early deaths resulting from AEs.

Grade 3 or higher AEs included pneumonia (20%), neutropenic fever (11%), diarrhea (6%), pyrexia (4%), cough (4%), and fatigue (2%). Common grade 3 or higher lab abnormalities included neutropenia (43%), anemia (11%), and thrombocytopenia (17%).

The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 criteria and 33% meeting the criteria of partial response in the presence of treatment-induced lymphocytosis.

The median duration of response was 16.2 months, the median progression-free survival (PFS) was 15.8 months, and the median overall survival was not reached.

Longer response duration in iNHL

The researchers evaluated idelalisib in 64 patients with iNHL. Lymphoma types included follicular lymphoma (59%), small lymphocytic lymphoma (17%), marginal zone lymphoma (9%), and lymphoplasmacytic lymphoma (14%).

Patients had a median age of 64 years (range, 32-91), 53% had bulky disease, and 58% had refractory disease. They had received a median of 4 prior therapies (range, 1-10).

The patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily. After 48 weeks, patients still benefitting from treatment (30%) were enrolled in an extension study.

The remaining 70% of patients discontinued treatment during the primary study. Nineteen percent of these patients discontinued due to AEs.

Grade 3 or higher AEs included pneumonia (17%), diarrhea (9%), peripheral edema (3%), fatigue (3%), rash (3%), pyrexia (3%), nausea (2%), and cough (2%). Grade 3 or higher lab abnormalities included AST elevation (20%), ALT elevation (23%), neutropenia (23%), thrombocytopenia (11%), and anemia (5%).

The overall response rate was 47%, with 1 patient (1.6%) achieving a complete response. The median duration of response was 18.4 months, and the median PFS was 7.6 months.

Short response, survival duration in MCL

The researchers evaluated idelalisib in 40 patients with relapsed or refractory MCL. The median age was 69 years (range, 52-83). Patients had received a median of 4 prior therapies (range, 1-14), and 43% were refractory to their most recent treatment.

Patients received idelalisib at doses ranging from 50 mg to 350 mg once or twice daily for a median of 3.5 months (range, 0.7-30.7). Six patients (15%) continued treatment for more than 48 weeks, although only 1 patient remains on treatment at present.

The 34 patients who discontinued the primary study did so because of progressive disease (60%), AEs (20%), withdrawn consent (3%), or investigator request (3%). Of the 6 patients who entered the extension trial, 4 ultimately discontinued due to progressive disease and 1 due to AEs.

Grade 3 or higher AEs included diarrhea (18%), decreased appetite (15%), pneumonia (10%), nausea (5%), fatigue (3%), and rash (3%). Grade 3 or higher lab abnormalities included ALT/AST elevations (20%), neutropenia (10%), thrombocytopenia (5%), and anemia (3%).

The overall response rate was 40%, with 5% of patients achieving a complete response. The median duration of response was 2.7 months, and the median PFS was 3.7 months.

Despite the modest duration of survival observed in these patients, the researchers believe the strong initial response to idelalisib suggests the drug could still prove useful in patients with MCL.

“[I]delalisib is unlikely to receive designation as a single-agent therapy in mantle cell lymphoma due to the short duration of response,” said study author Brad S. Kahl, MD, of the University of Wisconsin Carbone Cancer Center in Madison.

“The path forward will likely include administering it in combination with other agents or developing second-generation PI3 kinase inhibitors.”

Hematopoietic stem cells

in the bone marrow

Hematopoietic stem cells (HSCs) require a highly regulated rate of protein synthesis to function properly, according to research published in Nature.

Experiments showed that a ribosomal mutation decreases protein synthesis in HSCs, and deletion of a tumor suppressor gene increases protein synthesis.

But both changes result in impaired HSC function.

In mouse models, the mutation counteracted the effects of the deletion, which restored normal HSC function and delayed leukemogenesis.

“We unveiled new areas of cellular biology that no one has seen before,” said study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas.

“This finding not only tells us something new about stem cell regulation but opens up the ability to study differences in protein synthesis between many kinds of cells in the body. We believe there is an undiscovered world of biology that allows different kinds of cells to synthesize protein at different rates and in different ways, and that those differences are important for cellular survival.”

In a previous study, researchers discovered that, by modifying the antibiotic puromycin, they could measure protein synthesis in rare cells in vivo.

Dr Morrison and his colleagues realized they could adapt this reagent to measure protein synthesis in HSCs and other cells in the hematopoietic system.

Their analyses showed that different types of blood cells produced vastly different amounts of protein per hour. And HSCs, in particular, synthesized much less protein than other hematopoietic progenitors.

“This result suggests that blood-forming stem cells require a lower rate of protein synthesis as compared to other blood-forming cells,” Dr Morrison said.

He and his colleagues then generated mice with a mutation in a component of the ribosome (Rpl24^Bst/+ mice). HSCs in these mice had a 30% lower rate of protein production than controls.

The researchers observed the opposite effect when they deleted the tumor suppressor gene Pten in mouse HSCs. These mice saw a roughly 30% increase in protein production relative to controls.

However, as in the Rpl24^Bst/+ mice, HSC function was noticeably impaired in these animals.

Together, these observations suggest that HSCs require a highly regulated rate of protein synthesis, such that increases or decreases in that rate impair HSC function.

“Amazingly, when the ribosomal mutant mice and the Pten mutant mice were bred together, stem cell function returned to normal, and we greatly delayed, and in some instances entirely blocked, the development of leukemia,” Dr Morrison said.

“All of this happened because protein production in stem cells was returned to normal. It was as if two wrongs made a right.”

Hematopoietic stem cells

in the bone marrow

Hematopoietic stem cells (HSCs) require a highly regulated rate of protein synthesis to function properly, according to research published in Nature.

Experiments showed that a ribosomal mutation decreases protein synthesis in HSCs, and deletion of a tumor suppressor gene increases protein synthesis.

But both changes result in impaired HSC function.

In mouse models, the mutation counteracted the effects of the deletion, which restored normal HSC function and delayed leukemogenesis.

“We unveiled new areas of cellular biology that no one has seen before,” said study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas.

“This finding not only tells us something new about stem cell regulation but opens up the ability to study differences in protein synthesis between many kinds of cells in the body. We believe there is an undiscovered world of biology that allows different kinds of cells to synthesize protein at different rates and in different ways, and that those differences are important for cellular survival.”

In a previous study, researchers discovered that, by modifying the antibiotic puromycin, they could measure protein synthesis in rare cells in vivo.

Dr Morrison and his colleagues realized they could adapt this reagent to measure protein synthesis in HSCs and other cells in the hematopoietic system.

Their analyses showed that different types of blood cells produced vastly different amounts of protein per hour. And HSCs, in particular, synthesized much less protein than other hematopoietic progenitors.

“This result suggests that blood-forming stem cells require a lower rate of protein synthesis as compared to other blood-forming cells,” Dr Morrison said.

He and his colleagues then generated mice with a mutation in a component of the ribosome (Rpl24^Bst/+ mice). HSCs in these mice had a 30% lower rate of protein production than controls.

The researchers observed the opposite effect when they deleted the tumor suppressor gene Pten in mouse HSCs. These mice saw a roughly 30% increase in protein production relative to controls.

However, as in the Rpl24^Bst/+ mice, HSC function was noticeably impaired in these animals.

Together, these observations suggest that HSCs require a highly regulated rate of protein synthesis, such that increases or decreases in that rate impair HSC function.

“Amazingly, when the ribosomal mutant mice and the Pten mutant mice were bred together, stem cell function returned to normal, and we greatly delayed, and in some instances entirely blocked, the development of leukemia,” Dr Morrison said.

“All of this happened because protein production in stem cells was returned to normal. It was as if two wrongs made a right.”

Hematopoietic stem cells

in the bone marrow

Hematopoietic stem cells (HSCs) require a highly regulated rate of protein synthesis to function properly, according to research published in Nature.

Experiments showed that a ribosomal mutation decreases protein synthesis in HSCs, and deletion of a tumor suppressor gene increases protein synthesis.

But both changes result in impaired HSC function.

In mouse models, the mutation counteracted the effects of the deletion, which restored normal HSC function and delayed leukemogenesis.

“We unveiled new areas of cellular biology that no one has seen before,” said study author Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas.

“This finding not only tells us something new about stem cell regulation but opens up the ability to study differences in protein synthesis between many kinds of cells in the body. We believe there is an undiscovered world of biology that allows different kinds of cells to synthesize protein at different rates and in different ways, and that those differences are important for cellular survival.”

In a previous study, researchers discovered that, by modifying the antibiotic puromycin, they could measure protein synthesis in rare cells in vivo.

Dr Morrison and his colleagues realized they could adapt this reagent to measure protein synthesis in HSCs and other cells in the hematopoietic system.

Their analyses showed that different types of blood cells produced vastly different amounts of protein per hour. And HSCs, in particular, synthesized much less protein than other hematopoietic progenitors.

“This result suggests that blood-forming stem cells require a lower rate of protein synthesis as compared to other blood-forming cells,” Dr Morrison said.

He and his colleagues then generated mice with a mutation in a component of the ribosome (Rpl24^Bst/+ mice). HSCs in these mice had a 30% lower rate of protein production than controls.

The researchers observed the opposite effect when they deleted the tumor suppressor gene Pten in mouse HSCs. These mice saw a roughly 30% increase in protein production relative to controls.

However, as in the Rpl24^Bst/+ mice, HSC function was noticeably impaired in these animals.

Together, these observations suggest that HSCs require a highly regulated rate of protein synthesis, such that increases or decreases in that rate impair HSC function.

“Amazingly, when the ribosomal mutant mice and the Pten mutant mice were bred together, stem cell function returned to normal, and we greatly delayed, and in some instances entirely blocked, the development of leukemia,” Dr Morrison said.

“All of this happened because protein production in stem cells was returned to normal. It was as if two wrongs made a right.”

Doctor evaluating patient

Credit: CDC

A scoring system that rates symptoms of pulmonary dysfunction can help predict survival in patients with chronic graft-vs-host disease (GVHD), new research suggests.

The National Institutes of Health (NIH) devised a scoring system whereby patients can rate their breathing difficulties on a scale of 0 to 3.

In a study of nearly 500 patients with chronic GVHD, this system proved more effective in predicting survival than other measures of pulmonary dysfunction.

A patient’s score was significantly associated with the risk of overall survival (OS) and non-relapse mortality (NRM).

Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues reported these findings in Biology of Blood and Marrow Transplantation.

The researchers evaluated the utility of pulmonary function tests (PFTs) and symptom assessment in predicting the outcomes of 496 patients with chronic GVHD. The team looked at results of PFTs and the NIH lung scoring system, which has 2 parts.

One part is the NIH symptom-based lung score, which assigns the following numbers to breathing difficulties: 0 for no symptoms, 1 for shortness of breath climbing stairs, 2 for shortness of breath on flat ground, and 3 for shortness of breath at rest or requiring oxygen.

The second part of the system is the NIH PFT-based lung score, a lung function score calculated according to a patient’s forced expiratory volume in 1 second (FEV1) and diffusing capacity of carbon monoxide (DLCO), corrected for hemoglobin but not alveolar volume.

The researchers focused on a set of hypothesized associations between pulmonary measures and NRM, OS, patient-reported outcomes, and functional status.

The 7 measures of interest were:

1. Obstructive lung disease based on PFTs
2. Restrictive lung disease based on PFTs
3. NIH PFT-based lung score
4. NIH symptom-based lung score
5. Clinical diagnosis of bronchiolitis obliterans syndrome
6. Decrease in FEV1 or forced vital capacity (FVC) compared to enrollment
7. Worsening of NIH symptom-based lung score by 1 point or greater compared with the first recorded score.

The researchers found that only the NIH symptom-based lung score was significantly associated with NRM (P=0.02), OS (P=0.02), patient-reported symptoms (P<0.001), and functional status (P<0.001).

In addition, worsening of the NIH symptom-based lung score over time was associated with higher NRM and lower OS.

None of the other measures studied were significantly associated with OS or NRM, although some were associated with patient-reported symptoms.

“The [NIH symptom-based lung score] turned out to be the most predictive,” Dr Lee said. “It’s just a question [and], therefore, easy to do and cost-effective. No special equipment is involved.”

This suggests there’s a simple way for physicians to detect pulmonary dysfunction earlier, she added. A patient’s doctor could follow up on a poor score with tests to determine the cause of the problem and identify the appropriate treatment.

Doctor evaluating patient

Credit: CDC

A scoring system that rates symptoms of pulmonary dysfunction can help predict survival in patients with chronic graft-vs-host disease (GVHD), new research suggests.

The National Institutes of Health (NIH) devised a scoring system whereby patients can rate their breathing difficulties on a scale of 0 to 3.

In a study of nearly 500 patients with chronic GVHD, this system proved more effective in predicting survival than other measures of pulmonary dysfunction.

A patient’s score was significantly associated with the risk of overall survival (OS) and non-relapse mortality (NRM).

Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues reported these findings in Biology of Blood and Marrow Transplantation.

The researchers evaluated the utility of pulmonary function tests (PFTs) and symptom assessment in predicting the outcomes of 496 patients with chronic GVHD. The team looked at results of PFTs and the NIH lung scoring system, which has 2 parts.

One part is the NIH symptom-based lung score, which assigns the following numbers to breathing difficulties: 0 for no symptoms, 1 for shortness of breath climbing stairs, 2 for shortness of breath on flat ground, and 3 for shortness of breath at rest or requiring oxygen.

The second part of the system is the NIH PFT-based lung score, a lung function score calculated according to a patient’s forced expiratory volume in 1 second (FEV1) and diffusing capacity of carbon monoxide (DLCO), corrected for hemoglobin but not alveolar volume.

The researchers focused on a set of hypothesized associations between pulmonary measures and NRM, OS, patient-reported outcomes, and functional status.

The 7 measures of interest were:

1. Obstructive lung disease based on PFTs
2. Restrictive lung disease based on PFTs
3. NIH PFT-based lung score
4. NIH symptom-based lung score
5. Clinical diagnosis of bronchiolitis obliterans syndrome
6. Decrease in FEV1 or forced vital capacity (FVC) compared to enrollment
7. Worsening of NIH symptom-based lung score by 1 point or greater compared with the first recorded score.

The researchers found that only the NIH symptom-based lung score was significantly associated with NRM (P=0.02), OS (P=0.02), patient-reported symptoms (P<0.001), and functional status (P<0.001).

In addition, worsening of the NIH symptom-based lung score over time was associated with higher NRM and lower OS.

None of the other measures studied were significantly associated with OS or NRM, although some were associated with patient-reported symptoms.

“The [NIH symptom-based lung score] turned out to be the most predictive,” Dr Lee said. “It’s just a question [and], therefore, easy to do and cost-effective. No special equipment is involved.”

This suggests there’s a simple way for physicians to detect pulmonary dysfunction earlier, she added. A patient’s doctor could follow up on a poor score with tests to determine the cause of the problem and identify the appropriate treatment.

Doctor evaluating patient

Credit: CDC

A scoring system that rates symptoms of pulmonary dysfunction can help predict survival in patients with chronic graft-vs-host disease (GVHD), new research suggests.

The National Institutes of Health (NIH) devised a scoring system whereby patients can rate their breathing difficulties on a scale of 0 to 3.

In a study of nearly 500 patients with chronic GVHD, this system proved more effective in predicting survival than other measures of pulmonary dysfunction.

A patient’s score was significantly associated with the risk of overall survival (OS) and non-relapse mortality (NRM).

Stephanie Lee, MD, MPH, of the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues reported these findings in Biology of Blood and Marrow Transplantation.

The researchers evaluated the utility of pulmonary function tests (PFTs) and symptom assessment in predicting the outcomes of 496 patients with chronic GVHD. The team looked at results of PFTs and the NIH lung scoring system, which has 2 parts.

One part is the NIH symptom-based lung score, which assigns the following numbers to breathing difficulties: 0 for no symptoms, 1 for shortness of breath climbing stairs, 2 for shortness of breath on flat ground, and 3 for shortness of breath at rest or requiring oxygen.

The second part of the system is the NIH PFT-based lung score, a lung function score calculated according to a patient’s forced expiratory volume in 1 second (FEV1) and diffusing capacity of carbon monoxide (DLCO), corrected for hemoglobin but not alveolar volume.

The researchers focused on a set of hypothesized associations between pulmonary measures and NRM, OS, patient-reported outcomes, and functional status.

The 7 measures of interest were:

1. Obstructive lung disease based on PFTs
2. Restrictive lung disease based on PFTs
3. NIH PFT-based lung score
4. NIH symptom-based lung score
5. Clinical diagnosis of bronchiolitis obliterans syndrome
6. Decrease in FEV1 or forced vital capacity (FVC) compared to enrollment
7. Worsening of NIH symptom-based lung score by 1 point or greater compared with the first recorded score.

The researchers found that only the NIH symptom-based lung score was significantly associated with NRM (P=0.02), OS (P=0.02), patient-reported symptoms (P<0.001), and functional status (P<0.001).

In addition, worsening of the NIH symptom-based lung score over time was associated with higher NRM and lower OS.

None of the other measures studied were significantly associated with OS or NRM, although some were associated with patient-reported symptoms.

“The [NIH symptom-based lung score] turned out to be the most predictive,” Dr Lee said. “It’s just a question [and], therefore, easy to do and cost-effective. No special equipment is involved.”

This suggests there’s a simple way for physicians to detect pulmonary dysfunction earlier, she added. A patient’s doctor could follow up on a poor score with tests to determine the cause of the problem and identify the appropriate treatment.

Lab mice

Credit: Aaron Logan

Researchers have identified a cell that appears to be responsible for a particularly aggressive type of leukemia in mice.

The cell is a renin-expressing B-cell progenitor found in the bone marrow.

Renin cells, which are also present in the kidney, have traditionally been associated with the control of blood pressure and fluid balance in the body.

But investigators discovered renin progenitors in the bone marrow of mice with aggressive B-cell leukemia.

And they found evidence to suggest the leukemia originated from a mutation in these renin progenitors—specifically, deletion of RBP-J.

“We would now like to see if this is a relevant model of human disease,” said study author Brian C. Belyea, MD, of the University of Virginia (UVA) School of Medicine in Charlottesville.

“Our long-term goal is to identify cells at increased risk for leukemia in humans and, ultimately, develop strategies to monitor and eliminate these cells.”

Dr Belyea and his colleagues described their initial steps toward this goal in Nature Communications.

In a previous study, the researchers were investigating the effects of RBP-J deletion in mice. And they were surprised to find that, as the mice aged beyond 6 months, they developed signs of an aggressive form of precursor B-lymphoblastic leukemia.

So with the current study, the team wanted to characterize this leukemia. They set out to identify which cells in the bone marrow are capable of producing renin under normal circumstances and whether those cells might be the origin of the leukemia.

The investigators found that renin is expressed by a subset of B-cell progenitors in the mouse bone marrow, and these cells need RBP-J to differentiate.

Deleting RBP-J restrains lymphocyte differentiation, and the mutant cells undergo neoplastic transformation. The mice develop a B-cell leukemia characterized by multi-organ infiltration and resulting in early death.

Experiments showed the leukemia to be particularly hardy. The researchers placed the leukemic cells in a lab dish and found they continued to survive, and even thrive, without any assistance.

“People have been trying to grow leukemia cells in culture, even from patients, and they require other factors to survive, but not these,” said study author Maria Luisa S. Sequeira-Lopez, MD, of UVA.

“These are extremely aggressive in that they have developed a system to grow and survive no matter what,” added author Ariel Gomez, MD, also of UVA. “They have immortalized themselves.”

The researchers now want to determine if these findings will translate to humans. They believe it’s possible, as they were able to identify RBP-J mutations in 10 patients (of 44 screened) with hematologic malignancies. In fact, 5 of the patients had the same frameshift deletion.

Lab mice

Credit: Aaron Logan

Researchers have identified a cell that appears to be responsible for a particularly aggressive type of leukemia in mice.

The cell is a renin-expressing B-cell progenitor found in the bone marrow.

Renin cells, which are also present in the kidney, have traditionally been associated with the control of blood pressure and fluid balance in the body.

But investigators discovered renin progenitors in the bone marrow of mice with aggressive B-cell leukemia.

And they found evidence to suggest the leukemia originated from a mutation in these renin progenitors—specifically, deletion of RBP-J.

“We would now like to see if this is a relevant model of human disease,” said study author Brian C. Belyea, MD, of the University of Virginia (UVA) School of Medicine in Charlottesville.

“Our long-term goal is to identify cells at increased risk for leukemia in humans and, ultimately, develop strategies to monitor and eliminate these cells.”

Dr Belyea and his colleagues described their initial steps toward this goal in Nature Communications.

In a previous study, the researchers were investigating the effects of RBP-J deletion in mice. And they were surprised to find that, as the mice aged beyond 6 months, they developed signs of an aggressive form of precursor B-lymphoblastic leukemia.

So with the current study, the team wanted to characterize this leukemia. They set out to identify which cells in the bone marrow are capable of producing renin under normal circumstances and whether those cells might be the origin of the leukemia.

The investigators found that renin is expressed by a subset of B-cell progenitors in the mouse bone marrow, and these cells need RBP-J to differentiate.

Deleting RBP-J restrains lymphocyte differentiation, and the mutant cells undergo neoplastic transformation. The mice develop a B-cell leukemia characterized by multi-organ infiltration and resulting in early death.

Experiments showed the leukemia to be particularly hardy. The researchers placed the leukemic cells in a lab dish and found they continued to survive, and even thrive, without any assistance.

“People have been trying to grow leukemia cells in culture, even from patients, and they require other factors to survive, but not these,” said study author Maria Luisa S. Sequeira-Lopez, MD, of UVA.

“These are extremely aggressive in that they have developed a system to grow and survive no matter what,” added author Ariel Gomez, MD, also of UVA. “They have immortalized themselves.”

The researchers now want to determine if these findings will translate to humans. They believe it’s possible, as they were able to identify RBP-J mutations in 10 patients (of 44 screened) with hematologic malignancies. In fact, 5 of the patients had the same frameshift deletion.

Lab mice

Credit: Aaron Logan

Researchers have identified a cell that appears to be responsible for a particularly aggressive type of leukemia in mice.

The cell is a renin-expressing B-cell progenitor found in the bone marrow.

Renin cells, which are also present in the kidney, have traditionally been associated with the control of blood pressure and fluid balance in the body.

But investigators discovered renin progenitors in the bone marrow of mice with aggressive B-cell leukemia.

And they found evidence to suggest the leukemia originated from a mutation in these renin progenitors—specifically, deletion of RBP-J.

“We would now like to see if this is a relevant model of human disease,” said study author Brian C. Belyea, MD, of the University of Virginia (UVA) School of Medicine in Charlottesville.

“Our long-term goal is to identify cells at increased risk for leukemia in humans and, ultimately, develop strategies to monitor and eliminate these cells.”

Dr Belyea and his colleagues described their initial steps toward this goal in Nature Communications.

In a previous study, the researchers were investigating the effects of RBP-J deletion in mice. And they were surprised to find that, as the mice aged beyond 6 months, they developed signs of an aggressive form of precursor B-lymphoblastic leukemia.

So with the current study, the team wanted to characterize this leukemia. They set out to identify which cells in the bone marrow are capable of producing renin under normal circumstances and whether those cells might be the origin of the leukemia.

The investigators found that renin is expressed by a subset of B-cell progenitors in the mouse bone marrow, and these cells need RBP-J to differentiate.

Deleting RBP-J restrains lymphocyte differentiation, and the mutant cells undergo neoplastic transformation. The mice develop a B-cell leukemia characterized by multi-organ infiltration and resulting in early death.

Experiments showed the leukemia to be particularly hardy. The researchers placed the leukemic cells in a lab dish and found they continued to survive, and even thrive, without any assistance.

“People have been trying to grow leukemia cells in culture, even from patients, and they require other factors to survive, but not these,” said study author Maria Luisa S. Sequeira-Lopez, MD, of UVA.

“These are extremely aggressive in that they have developed a system to grow and survive no matter what,” added author Ariel Gomez, MD, also of UVA. “They have immortalized themselves.”

The researchers now want to determine if these findings will translate to humans. They believe it’s possible, as they were able to identify RBP-J mutations in 10 patients (of 44 screened) with hematologic malignancies. In fact, 5 of the patients had the same frameshift deletion.

A sickled red blood cell

and a normal one

Credit: Betty Pace

There may be a simple reason why genetic screening has failed to fulfill the promise of preventing sickle cell disease (SCD).

According to an article published in JAMA, it’s a lack of communication.

We’ve long had the technical capacity to screen individuals for the sickle cell trait (SCT). Yet few individuals of child-bearing age who were born in the US actually know their SCT status.

So they aren’t aware that they might pass SCT or SCD down to their children.

And this may boil down to a lack of communication among healthcare professionals, patients, and family members.

“[P]arents are routinely notified by NBS [newborn screening] programs if their child has SCD, but only 37% are notified if their child has SCT,” said author Barry Zuckerman, MD, of Boston Medical Center in Massachusetts.

Even if parents do receive SCT screening results, we don’t know whether they understand the implications or share them with their child. And counseling or referrals to genetic counsellors are not provided in a standard fashion.

Furthermore, although NBS programs notify primary care physicians of screening results at the time of birth, results may not be readily available during routine clinic visits, and patients may not have the same physician throughout their childhood.

The lack of knowledge regarding SCT status represents a missed opportunity to provide appropriate health and prenatal counseling and testing, according to Dr Zuckerman and his colleagues.

They said that timely knowledge of genetic vulnerability and genetic counseling are necessary for informed decision-making with regard to reproduction. It is important to increase the number of adolescents and young adults who know their SCT status to decrease the number of individuals inheriting SCD.

To increase awareness of SCT status and facilitate informed decision-making about reproductive options, we must do 2 things, according to the authors.

First, the results of positive screens for SCT must be communicated to primary care clinicians, recorded in the patient’s medical record as part of a problem list, and shared with parents and the individual.

And second, we must provide effective communication and information through genetic counseling on reproductive options for those with SCT.

The authors also stressed that schools and community organizations have potentially important roles in communicating the importance of SCT status to adolescents and young adults. And by working together, the healthcare system, schools, and community organizations may be able to improve SCT knowledge and awareness.

A sickled red blood cell

and a normal one

Credit: Betty Pace

There may be a simple reason why genetic screening has failed to fulfill the promise of preventing sickle cell disease (SCD).

According to an article published in JAMA, it’s a lack of communication.

We’ve long had the technical capacity to screen individuals for the sickle cell trait (SCT). Yet few individuals of child-bearing age who were born in the US actually know their SCT status.

So they aren’t aware that they might pass SCT or SCD down to their children.

And this may boil down to a lack of communication among healthcare professionals, patients, and family members.

“[P]arents are routinely notified by NBS [newborn screening] programs if their child has SCD, but only 37% are notified if their child has SCT,” said author Barry Zuckerman, MD, of Boston Medical Center in Massachusetts.

Even if parents do receive SCT screening results, we don’t know whether they understand the implications or share them with their child. And counseling or referrals to genetic counsellors are not provided in a standard fashion.

Furthermore, although NBS programs notify primary care physicians of screening results at the time of birth, results may not be readily available during routine clinic visits, and patients may not have the same physician throughout their childhood.

The lack of knowledge regarding SCT status represents a missed opportunity to provide appropriate health and prenatal counseling and testing, according to Dr Zuckerman and his colleagues.

They said that timely knowledge of genetic vulnerability and genetic counseling are necessary for informed decision-making with regard to reproduction. It is important to increase the number of adolescents and young adults who know their SCT status to decrease the number of individuals inheriting SCD.

To increase awareness of SCT status and facilitate informed decision-making about reproductive options, we must do 2 things, according to the authors.

First, the results of positive screens for SCT must be communicated to primary care clinicians, recorded in the patient’s medical record as part of a problem list, and shared with parents and the individual.

And second, we must provide effective communication and information through genetic counseling on reproductive options for those with SCT.

The authors also stressed that schools and community organizations have potentially important roles in communicating the importance of SCT status to adolescents and young adults. And by working together, the healthcare system, schools, and community organizations may be able to improve SCT knowledge and awareness.

A sickled red blood cell

and a normal one

Credit: Betty Pace

There may be a simple reason why genetic screening has failed to fulfill the promise of preventing sickle cell disease (SCD).

According to an article published in JAMA, it’s a lack of communication.

We’ve long had the technical capacity to screen individuals for the sickle cell trait (SCT). Yet few individuals of child-bearing age who were born in the US actually know their SCT status.

So they aren’t aware that they might pass SCT or SCD down to their children.

And this may boil down to a lack of communication among healthcare professionals, patients, and family members.

“[P]arents are routinely notified by NBS [newborn screening] programs if their child has SCD, but only 37% are notified if their child has SCT,” said author Barry Zuckerman, MD, of Boston Medical Center in Massachusetts.

Even if parents do receive SCT screening results, we don’t know whether they understand the implications or share them with their child. And counseling or referrals to genetic counsellors are not provided in a standard fashion.

Furthermore, although NBS programs notify primary care physicians of screening results at the time of birth, results may not be readily available during routine clinic visits, and patients may not have the same physician throughout their childhood.

The lack of knowledge regarding SCT status represents a missed opportunity to provide appropriate health and prenatal counseling and testing, according to Dr Zuckerman and his colleagues.

They said that timely knowledge of genetic vulnerability and genetic counseling are necessary for informed decision-making with regard to reproduction. It is important to increase the number of adolescents and young adults who know their SCT status to decrease the number of individuals inheriting SCD.

To increase awareness of SCT status and facilitate informed decision-making about reproductive options, we must do 2 things, according to the authors.

First, the results of positive screens for SCT must be communicated to primary care clinicians, recorded in the patient’s medical record as part of a problem list, and shared with parents and the individual.

And second, we must provide effective communication and information through genetic counseling on reproductive options for those with SCT.

The authors also stressed that schools and community organizations have potentially important roles in communicating the importance of SCT status to adolescents and young adults. And by working together, the healthcare system, schools, and community organizations may be able to improve SCT knowledge and awareness.