The Immunization Action Coalition (IAC) works in cadence with the Centers for Disease Control and Prevention (CDC) to offer health care professionals in both the public and private sectors the most up-to-date immunization information available in one retrievable location. This well established website, http://www.immunize.org, serves more than 14,000 visitors every day.

Talking About Vaccines provides research and guidelines by an assortment of nationally recognized institutions, including the IAC, CDC, and many others in response to common concerns.

Within Clinic Resources, users can access how-to documents on providing vaccines at a clinic or nontraditional setting. Also available are patient and staff handouts, including indexed vaccines (eg, human papillomavirus and tetanus) and topics such as needle safety.

The Immunization Action Coalition (IAC) works in cadence with the Centers for Disease Control and Prevention (CDC) to offer health care professionals in both the public and private sectors the most up-to-date immunization information available in one retrievable location. This well established website, http://www.immunize.org, serves more than 14,000 visitors every day.

Talking About Vaccines provides research and guidelines by an assortment of nationally recognized institutions, including the IAC, CDC, and many others in response to common concerns.

Within Clinic Resources, users can access how-to documents on providing vaccines at a clinic or nontraditional setting. Also available are patient and staff handouts, including indexed vaccines (eg, human papillomavirus and tetanus) and topics such as needle safety.

The Immunization Action Coalition (IAC) works in cadence with the Centers for Disease Control and Prevention (CDC) to offer health care professionals in both the public and private sectors the most up-to-date immunization information available in one retrievable location. This well established website, http://www.immunize.org, serves more than 14,000 visitors every day.

Talking About Vaccines provides research and guidelines by an assortment of nationally recognized institutions, including the IAC, CDC, and many others in response to common concerns.

Within Clinic Resources, users can access how-to documents on providing vaccines at a clinic or nontraditional setting. Also available are patient and staff handouts, including indexed vaccines (eg, human papillomavirus and tetanus) and topics such as needle safety.

Preparing for transplant

Credit: Chad McNeeley

NEW YORK—A debate on the pros and cons of upfront transplant in symptomatic multiple myeloma (MM) yielded a split decision from the audience during the NCCN 9th Annual Congress: Hematologic Malignancies.

Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York, argued for upfront transplant, pointing out that long-term MM survivors have transplant as upfront therapy.

Kenneth Anderson, MD, of Dana Farber/Brigham and Women’s Cancer Center in Boston, took the stance that, in the past 10 years, there has been a

revolution in novel therapies that has significantly improved survival in MM.

For upfront transplant

Dr Giralt cited the 36-month follow-up of the E4A03 landmark analysis of patients who went off therapy after 4 cycles of lenalidomide/dexamethasone to pursue early stem cell transplant and those who continued treatment until disease progression.

Regardless of whether the patients were younger than 65 years or between 65 and 70, the patients who had an early transplant had superior progression-free survival (PFS) and overall survival (OS) compared to those who did not.

Dr Giralt added that bortezomib should be a component of induction therapy prior to autologous stem cell transplant (ASCT). Even though there is no survival benefit with bortezomib-based regimens, he said, there is significant improvement in PFS, as shown in a meta-analysis of phase 3 European studies.

The E4A03 landmark study also determined that the more intense the treatment, the better the outcome. So patients with double ASCT had a significantly longer PFS than patients who only had a single transplant.

This held true for OS as well, and included patients with 17p deletion and/or t(4;14) who failed to achieve complete remission after bortezomib-based induction regimens.

An analysis of 27,987 MM patients with a median age of 68 years (range, 19 to 90) revealed that of the patients who survived 10 years or more, 16.5% had ASCT as part of their initial therapy.

Dr Giralt concluded that the preponderance of evidence supports high-dose melphalan and ASCT as upfront consolidation therapy for MM. And until results of randomized trials investigating combination therapies are reported, melphalan consolidation should be considered the standard of care for all eligible patients with MM.

Against upfront transplant

Dr Anderson countered with data showing limited or no improvement in survival with ASCT, including evidence from studies by Attal, Fermand, Blade, Child, and Barlogie.

ASCT confers only modest PFS advantage, he said, showing results of the Barlogie study in which patients undergoing ASCT had a 25-month PFS, compared with a 21-month PFS with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone).

“In the last 10 to 15 years, there has been a revolution in myeloma,” Dr Anderson said. “We have a lot of novel agents here today, and we have even more coming. It’s a hugely exciting time.”

Dr Anderson pointed out that since the introduction of novel agents, survival has improved between 2006 and 2010, compared to the period between 2001 and 2005, and particularly in patients older than 65 years (P=0.001).

Transplant has also changed, he said. Novel therapies have been integrated into the transplant paradigm, either before, as induction and consolidation therapy, or after, as maintenance. He indicated that this begs the question as to whether we really need the transplant component.

There has also been unprecedented use of triplets in combination therapy, Dr Anderson said, resulting in overall response rates upwards of 90%. For example, carfilzomib in combination with lenalidomide and dexamethasone prompted an overall response rate of 94%, with a stringent complete response (CR), CR, and near CR of 53%.

“It’s a new day in myeloma,” he said. “It’s taken us a long time, but we’re worrying about minimal residual disease (MRD) now. We’re worried about getting to the endpoint of 1 myeloma cell in 1 million normal cells.”

The point is, he added, that with novel therapies, such as carfilzomib, lenalidomide, and dexamethasone, patients who achieve a complete response can become MRD negative, suggesting an unprecedented extent of response without transplant.

MRD negativity may also be accomplished with oral agents, such as ixazomib. The depth of response with ixazomib increases over the course of treatment, with 27% achieving stringent CR or CR with a median duration of response of 13.8 months, and 82% of patients attaining MRD-negative status.

“In the absence of transplant,” Dr Anderson said, “this is an unprecedented response.”

Dr Anderson also pointed out that in the era of novel agents, there is no difference in outcome between early or delayed transplant. The 4-year OS in transplant-eligible patients who received initial therapy with lenalidomide was 80%, regardless of the timing of ASCT.

And in one trial, patients who received a delayed transplant fared better in OS than those transplanted early.

Dr Anderson said there is a parallel, international phase 3 study underway (IFM/DFCI2009) that will provide an answer to the debate on upfront transplant in the not-too-distant future.

Preparing for transplant

Credit: Chad McNeeley

NEW YORK—A debate on the pros and cons of upfront transplant in symptomatic multiple myeloma (MM) yielded a split decision from the audience during the NCCN 9th Annual Congress: Hematologic Malignancies.

Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York, argued for upfront transplant, pointing out that long-term MM survivors have transplant as upfront therapy.

Kenneth Anderson, MD, of Dana Farber/Brigham and Women’s Cancer Center in Boston, took the stance that, in the past 10 years, there has been a

revolution in novel therapies that has significantly improved survival in MM.

For upfront transplant

Dr Giralt cited the 36-month follow-up of the E4A03 landmark analysis of patients who went off therapy after 4 cycles of lenalidomide/dexamethasone to pursue early stem cell transplant and those who continued treatment until disease progression.

Regardless of whether the patients were younger than 65 years or between 65 and 70, the patients who had an early transplant had superior progression-free survival (PFS) and overall survival (OS) compared to those who did not.

Dr Giralt added that bortezomib should be a component of induction therapy prior to autologous stem cell transplant (ASCT). Even though there is no survival benefit with bortezomib-based regimens, he said, there is significant improvement in PFS, as shown in a meta-analysis of phase 3 European studies.

The E4A03 landmark study also determined that the more intense the treatment, the better the outcome. So patients with double ASCT had a significantly longer PFS than patients who only had a single transplant.

This held true for OS as well, and included patients with 17p deletion and/or t(4;14) who failed to achieve complete remission after bortezomib-based induction regimens.

An analysis of 27,987 MM patients with a median age of 68 years (range, 19 to 90) revealed that of the patients who survived 10 years or more, 16.5% had ASCT as part of their initial therapy.

Dr Giralt concluded that the preponderance of evidence supports high-dose melphalan and ASCT as upfront consolidation therapy for MM. And until results of randomized trials investigating combination therapies are reported, melphalan consolidation should be considered the standard of care for all eligible patients with MM.

Against upfront transplant

Dr Anderson countered with data showing limited or no improvement in survival with ASCT, including evidence from studies by Attal, Fermand, Blade, Child, and Barlogie.

ASCT confers only modest PFS advantage, he said, showing results of the Barlogie study in which patients undergoing ASCT had a 25-month PFS, compared with a 21-month PFS with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone).

“In the last 10 to 15 years, there has been a revolution in myeloma,” Dr Anderson said. “We have a lot of novel agents here today, and we have even more coming. It’s a hugely exciting time.”

Dr Anderson pointed out that since the introduction of novel agents, survival has improved between 2006 and 2010, compared to the period between 2001 and 2005, and particularly in patients older than 65 years (P=0.001).

Transplant has also changed, he said. Novel therapies have been integrated into the transplant paradigm, either before, as induction and consolidation therapy, or after, as maintenance. He indicated that this begs the question as to whether we really need the transplant component.

There has also been unprecedented use of triplets in combination therapy, Dr Anderson said, resulting in overall response rates upwards of 90%. For example, carfilzomib in combination with lenalidomide and dexamethasone prompted an overall response rate of 94%, with a stringent complete response (CR), CR, and near CR of 53%.

“It’s a new day in myeloma,” he said. “It’s taken us a long time, but we’re worrying about minimal residual disease (MRD) now. We’re worried about getting to the endpoint of 1 myeloma cell in 1 million normal cells.”

The point is, he added, that with novel therapies, such as carfilzomib, lenalidomide, and dexamethasone, patients who achieve a complete response can become MRD negative, suggesting an unprecedented extent of response without transplant.

MRD negativity may also be accomplished with oral agents, such as ixazomib. The depth of response with ixazomib increases over the course of treatment, with 27% achieving stringent CR or CR with a median duration of response of 13.8 months, and 82% of patients attaining MRD-negative status.

“In the absence of transplant,” Dr Anderson said, “this is an unprecedented response.”

Dr Anderson also pointed out that in the era of novel agents, there is no difference in outcome between early or delayed transplant. The 4-year OS in transplant-eligible patients who received initial therapy with lenalidomide was 80%, regardless of the timing of ASCT.

And in one trial, patients who received a delayed transplant fared better in OS than those transplanted early.

Dr Anderson said there is a parallel, international phase 3 study underway (IFM/DFCI2009) that will provide an answer to the debate on upfront transplant in the not-too-distant future.

Preparing for transplant

Credit: Chad McNeeley

NEW YORK—A debate on the pros and cons of upfront transplant in symptomatic multiple myeloma (MM) yielded a split decision from the audience during the NCCN 9th Annual Congress: Hematologic Malignancies.

Sergio Giralt, MD, of Memorial Sloan Kettering Cancer Center in New York, argued for upfront transplant, pointing out that long-term MM survivors have transplant as upfront therapy.

Kenneth Anderson, MD, of Dana Farber/Brigham and Women’s Cancer Center in Boston, took the stance that, in the past 10 years, there has been a

revolution in novel therapies that has significantly improved survival in MM.

For upfront transplant

Dr Giralt cited the 36-month follow-up of the E4A03 landmark analysis of patients who went off therapy after 4 cycles of lenalidomide/dexamethasone to pursue early stem cell transplant and those who continued treatment until disease progression.

Regardless of whether the patients were younger than 65 years or between 65 and 70, the patients who had an early transplant had superior progression-free survival (PFS) and overall survival (OS) compared to those who did not.

Dr Giralt added that bortezomib should be a component of induction therapy prior to autologous stem cell transplant (ASCT). Even though there is no survival benefit with bortezomib-based regimens, he said, there is significant improvement in PFS, as shown in a meta-analysis of phase 3 European studies.

The E4A03 landmark study also determined that the more intense the treatment, the better the outcome. So patients with double ASCT had a significantly longer PFS than patients who only had a single transplant.

This held true for OS as well, and included patients with 17p deletion and/or t(4;14) who failed to achieve complete remission after bortezomib-based induction regimens.

An analysis of 27,987 MM patients with a median age of 68 years (range, 19 to 90) revealed that of the patients who survived 10 years or more, 16.5% had ASCT as part of their initial therapy.

Dr Giralt concluded that the preponderance of evidence supports high-dose melphalan and ASCT as upfront consolidation therapy for MM. And until results of randomized trials investigating combination therapies are reported, melphalan consolidation should be considered the standard of care for all eligible patients with MM.

Against upfront transplant

Dr Anderson countered with data showing limited or no improvement in survival with ASCT, including evidence from studies by Attal, Fermand, Blade, Child, and Barlogie.

ASCT confers only modest PFS advantage, he said, showing results of the Barlogie study in which patients undergoing ASCT had a 25-month PFS, compared with a 21-month PFS with VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone).

“In the last 10 to 15 years, there has been a revolution in myeloma,” Dr Anderson said. “We have a lot of novel agents here today, and we have even more coming. It’s a hugely exciting time.”

Dr Anderson pointed out that since the introduction of novel agents, survival has improved between 2006 and 2010, compared to the period between 2001 and 2005, and particularly in patients older than 65 years (P=0.001).

Transplant has also changed, he said. Novel therapies have been integrated into the transplant paradigm, either before, as induction and consolidation therapy, or after, as maintenance. He indicated that this begs the question as to whether we really need the transplant component.

There has also been unprecedented use of triplets in combination therapy, Dr Anderson said, resulting in overall response rates upwards of 90%. For example, carfilzomib in combination with lenalidomide and dexamethasone prompted an overall response rate of 94%, with a stringent complete response (CR), CR, and near CR of 53%.

“It’s a new day in myeloma,” he said. “It’s taken us a long time, but we’re worrying about minimal residual disease (MRD) now. We’re worried about getting to the endpoint of 1 myeloma cell in 1 million normal cells.”

The point is, he added, that with novel therapies, such as carfilzomib, lenalidomide, and dexamethasone, patients who achieve a complete response can become MRD negative, suggesting an unprecedented extent of response without transplant.

MRD negativity may also be accomplished with oral agents, such as ixazomib. The depth of response with ixazomib increases over the course of treatment, with 27% achieving stringent CR or CR with a median duration of response of 13.8 months, and 82% of patients attaining MRD-negative status.

“In the absence of transplant,” Dr Anderson said, “this is an unprecedented response.”

Dr Anderson also pointed out that in the era of novel agents, there is no difference in outcome between early or delayed transplant. The 4-year OS in transplant-eligible patients who received initial therapy with lenalidomide was 80%, regardless of the timing of ASCT.

And in one trial, patients who received a delayed transplant fared better in OS than those transplanted early.

Dr Anderson said there is a parallel, international phase 3 study underway (IFM/DFCI2009) that will provide an answer to the debate on upfront transplant in the not-too-distant future.

Multiple myeloma

PHILADELPHIA—A drug that targets the ribosome may be active in a broad range of hematologic malignancies, researchers say.

The drug, CX-5461, inhibits the protein RNA polymerase I (Pol I), which is consistently upregulated in hematologic and other cancers.

CX-5461 significantly prolonged survival in mouse models of refractory acute myeloid leukemia (AML) and multiple myeloma (MM). It also synergized with everolimus to extend survival in mice with B-cell lymphoma.

Furthermore, the drug did not elicit severe adverse effects.

“We were excited to find that therapeutic doses of CX-5461 had little effect on normal cells in our experiments,” said Ross D. Hannan, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia,

“Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called house-keeping protein that is essential to all cells for survival.”

Dr Hannan and his colleagues presented these findings in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

The researchers previously showed that cancer cells are much more dependent on ribosome biogenesis than normal cells. And blocking the accelerated reading of ribosomal genes in mice—using CX5461—can cause lymphoma and leukemia cells to die, while sparing normal cells.

With their latest research, the group expanded upon these findings by testing CX-5461 in MLL-driven AML, V*κ-Myc-driven MM, and Eμ-Myc lymphoma.

They found that CX-5461 improved overall survival in MLL/ENL Nras leukemic mice, compared to placebo and standard therapy. The median survival was 17 days for vehicle-treated mice, 21 days for mice treated with cytarabine and doxorubicin, and 36 days for mice that received CX-5461 (P<0.0001 for vehicle vs CX-5461).

CX-5461 treated MLL-driven AML by inducing apoptosis, delaying cell-cycle progression, and promoting differentiation.

The researchers also found the therapeutic benefit of CX-5461 is not p53-dependent, which contradicts their previous findings. Human AML cell lines and primary patient samples were sensitive to CX-5461 independent of p53 status.

And MLL/ENL Nras p53^-/- leukemic mice had significantly prolonged survival when treated with CX-5461, compared to vehicle-treated controls. The median survival was 11 days and 24 days, respectively (P<0.0001).

Likewise, CX-5461 significantly prolonged survival in mice bearing V*κ-Myc MM. The median survival was 103.5 days for controls and 175 days for mice that received CX-5461 (P<0.0001).

Finally, the researchers showed that CX-5461 synergizes with everolimus to treat Eμ-Myc lymphoma. The median survival was 15 days in control mice, 18 days in mice that received everolimus, 32 days in mice treated with CX-5461, and 54 days in mice that received both drugs (P<0.0001 for CX-5461 vs the combination).

“These results provide further rationale for the first-in-human phase 1 clinical trial that we initiated in July 2013 testing CX-5461 for patients with advanced hematological malignancies, including AML and multiple myeloma,” Dr Hannan said.

His group’s preclinical research was funded by the National Health and Medical Research Council, Australia; the Leukaemia Foundation of Australia; and Cancer Council Victoria, Melbourne, Australia. Senhwa Biosciences, the makers of CX-5461, provided the drug.

Multiple myeloma

PHILADELPHIA—A drug that targets the ribosome may be active in a broad range of hematologic malignancies, researchers say.

The drug, CX-5461, inhibits the protein RNA polymerase I (Pol I), which is consistently upregulated in hematologic and other cancers.

CX-5461 significantly prolonged survival in mouse models of refractory acute myeloid leukemia (AML) and multiple myeloma (MM). It also synergized with everolimus to extend survival in mice with B-cell lymphoma.

Furthermore, the drug did not elicit severe adverse effects.

“We were excited to find that therapeutic doses of CX-5461 had little effect on normal cells in our experiments,” said Ross D. Hannan, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia,

“Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called house-keeping protein that is essential to all cells for survival.”

Dr Hannan and his colleagues presented these findings in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

The researchers previously showed that cancer cells are much more dependent on ribosome biogenesis than normal cells. And blocking the accelerated reading of ribosomal genes in mice—using CX5461—can cause lymphoma and leukemia cells to die, while sparing normal cells.

With their latest research, the group expanded upon these findings by testing CX-5461 in MLL-driven AML, V*κ-Myc-driven MM, and Eμ-Myc lymphoma.

They found that CX-5461 improved overall survival in MLL/ENL Nras leukemic mice, compared to placebo and standard therapy. The median survival was 17 days for vehicle-treated mice, 21 days for mice treated with cytarabine and doxorubicin, and 36 days for mice that received CX-5461 (P<0.0001 for vehicle vs CX-5461).

CX-5461 treated MLL-driven AML by inducing apoptosis, delaying cell-cycle progression, and promoting differentiation.

The researchers also found the therapeutic benefit of CX-5461 is not p53-dependent, which contradicts their previous findings. Human AML cell lines and primary patient samples were sensitive to CX-5461 independent of p53 status.

And MLL/ENL Nras p53^-/- leukemic mice had significantly prolonged survival when treated with CX-5461, compared to vehicle-treated controls. The median survival was 11 days and 24 days, respectively (P<0.0001).

Likewise, CX-5461 significantly prolonged survival in mice bearing V*κ-Myc MM. The median survival was 103.5 days for controls and 175 days for mice that received CX-5461 (P<0.0001).

Finally, the researchers showed that CX-5461 synergizes with everolimus to treat Eμ-Myc lymphoma. The median survival was 15 days in control mice, 18 days in mice that received everolimus, 32 days in mice treated with CX-5461, and 54 days in mice that received both drugs (P<0.0001 for CX-5461 vs the combination).

“These results provide further rationale for the first-in-human phase 1 clinical trial that we initiated in July 2013 testing CX-5461 for patients with advanced hematological malignancies, including AML and multiple myeloma,” Dr Hannan said.

His group’s preclinical research was funded by the National Health and Medical Research Council, Australia; the Leukaemia Foundation of Australia; and Cancer Council Victoria, Melbourne, Australia. Senhwa Biosciences, the makers of CX-5461, provided the drug.

Multiple myeloma

PHILADELPHIA—A drug that targets the ribosome may be active in a broad range of hematologic malignancies, researchers say.

The drug, CX-5461, inhibits the protein RNA polymerase I (Pol I), which is consistently upregulated in hematologic and other cancers.

CX-5461 significantly prolonged survival in mouse models of refractory acute myeloid leukemia (AML) and multiple myeloma (MM). It also synergized with everolimus to extend survival in mice with B-cell lymphoma.

Furthermore, the drug did not elicit severe adverse effects.

“We were excited to find that therapeutic doses of CX-5461 had little effect on normal cells in our experiments,” said Ross D. Hannan, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia,

“Prior to these studies, few people would have guessed that such a therapeutic window could be obtained by targeting a so-called house-keeping protein that is essential to all cells for survival.”

Dr Hannan and his colleagues presented these findings in a poster at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

The researchers previously showed that cancer cells are much more dependent on ribosome biogenesis than normal cells. And blocking the accelerated reading of ribosomal genes in mice—using CX5461—can cause lymphoma and leukemia cells to die, while sparing normal cells.

With their latest research, the group expanded upon these findings by testing CX-5461 in MLL-driven AML, V*κ-Myc-driven MM, and Eμ-Myc lymphoma.

They found that CX-5461 improved overall survival in MLL/ENL Nras leukemic mice, compared to placebo and standard therapy. The median survival was 17 days for vehicle-treated mice, 21 days for mice treated with cytarabine and doxorubicin, and 36 days for mice that received CX-5461 (P<0.0001 for vehicle vs CX-5461).

CX-5461 treated MLL-driven AML by inducing apoptosis, delaying cell-cycle progression, and promoting differentiation.

The researchers also found the therapeutic benefit of CX-5461 is not p53-dependent, which contradicts their previous findings. Human AML cell lines and primary patient samples were sensitive to CX-5461 independent of p53 status.

And MLL/ENL Nras p53^-/- leukemic mice had significantly prolonged survival when treated with CX-5461, compared to vehicle-treated controls. The median survival was 11 days and 24 days, respectively (P<0.0001).

Likewise, CX-5461 significantly prolonged survival in mice bearing V*κ-Myc MM. The median survival was 103.5 days for controls and 175 days for mice that received CX-5461 (P<0.0001).

Finally, the researchers showed that CX-5461 synergizes with everolimus to treat Eμ-Myc lymphoma. The median survival was 15 days in control mice, 18 days in mice that received everolimus, 32 days in mice treated with CX-5461, and 54 days in mice that received both drugs (P<0.0001 for CX-5461 vs the combination).

“These results provide further rationale for the first-in-human phase 1 clinical trial that we initiated in July 2013 testing CX-5461 for patients with advanced hematological malignancies, including AML and multiple myeloma,” Dr Hannan said.

His group’s preclinical research was funded by the National Health and Medical Research Council, Australia; the Leukaemia Foundation of Australia; and Cancer Council Victoria, Melbourne, Australia. Senhwa Biosciences, the makers of CX-5461, provided the drug.

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

Delaying kidney transplantation to allow for quiescence of systemic lupus erythematosus–related immune activity in patients with lupus nephritis and end-stage renal disease does not appear to improve graft outcomes, according to an analysis of national surveillance data.

Of 4,743 transplant recipients with lupus nephritis and end-stage renal disease (LN-ESRD), 1,239 experienced graft failure. Overall, wait times of 3-12 months and 12-24 months were associated with 25% and 37% increased risk of graft failure, respectively, compared with wait times of less than 3 months, after adjustment for age, race, insurance, hemoglobin, and donor type.

A similar pattern was seen in white patients, except that wait times of more than 36 months in white patients were associated with a near doubling of graft failure risk (hazard ratio, 1.98), Laura C. Plantinga of Emory University, Atlanta, and her colleagues reported (Arthritis Care Res. 2014 Sept. 23 [doi:10.1002/acr.22482]).

Among black patients, longer wait times were not associated with graft failure in the adjusted analysis, and, in fact, there was a nonstatistically significant suggestion of a protective effect for wait time of 2 years or more. This finding may reflect unexplained differences in disease pathology between white and black LN-ESRD patients, the investigators said, adding that there was no increased risk of graft failure in black patients who were transplanted early.

“Our results suggest U.S. recommendations for transplantation in LN-ESRD may not align with evidence from the target population,” they said, noting that the results should be considered hypotheses-generating because of the limitations of the study and that additional study is needed to examine the potential confounding effects of clinically recognized SLE activity on the associations observed in this study.

Some of the investigators were supported through grants from the National Institutes of Health.

National Suicide Prevention Day fell on Sept. 10 this year, surrounded by National Suicide Prevention Week Sept. 8-14. The conversation, as I’m sure everyone noticed, was focused on the suicide of actor Robin Williams. As we move out a few weeks, my patients – especially those who have contemplated ending their own lives – continue to talk about this tragic loss.

The fear is that the suicide of a celebrity will lead to an increase in the suicide rate in the general public – copycat suicides, if you will. In the month after Marilyn Monroe died of an overdose in 1962, the suicide rate rose by more than 10%. On the other hand, the death of a celebrity may lead to a decrease in the suicide rate, as happened after Kurt Cobain’s death from a self-inflicted gunshot wound in 1994. In the period after Cobain’s death, an effort was made to publicize resources for those who need help. The suicide rate dropped, while calls to hotlines rose.

After Robin Williams’ death, my own social media feeds were full of ads for the National Suicide Prevention Lifeline (NSPL), a hotline with the number 1-800-273-TALK. There are other hotlines, but this was the one I saw most. I wanted to learn about suicide hotlines, so I did a few things: I asked readers of our Shrink Rap blog to tell me about their experiences, and I called the hotline myself to see if I could learn about the structure of the organization, what resources they had to offer a distraught caller, and whether there had been a change in the number of calls they’d received in the time following Mr. Williams’ death.

I called from my cell phone, which is registered in Maryland, while sitting in my home in Baltimore City. The call was routed to Grassroots Crisis Intervention Center in Columbia, Md. Google Maps tells me the center is 25 miles from my house, and it would take me 32 minutes to drive there. In addition to being part of a network of 160 hotline centers across the country, Grassroots has a walk-in crisis center and a mobile treatment center, and is adjacent to a homeless shelter.

“Most of the people who call the National Suicide Prevention Lifeline are suicidal,” said Nicole DeChirico, director of crisis intervention services for Grassroots. “There is a gradation in suicidal thinking, but about 90% of our callers are considering it.”

“We first form rapport, and then we try to quickly assess if an attempt has already been made, and if they are in any danger. We use the assessment of suicidality that is put out by the NSPL. It’s a structured template that is used as a guideline.”

Ms. DeChirico noted that the people who man the hotlines have bachelor’s or master’s degrees – often in psychology, social work, counseling, or education. If feasible, a Safety Planning Intervention is implemented, based on the work of Barbara Stanley, Ph.D., at Columbia University in New York.

“We talk to people about what they need to do to feel safe. If they allow it, we set up a follow-up call. Of the total number of people who have attempted suicide once in the past and lived, 90%-96% never go on to attempt suicide again,” Ms. DeChirico noted. Suicide is a time-limited acute crisis.”

The Grassroots team can see patients on site while they wait for appointments with an outpatient clinician, and can send a mobile crisis team to those who need it if they are in the county served by the organization. I wondered if all 160 agencies that received calls from the NSPL could also provide crisis services.

Marcia Epstein, LMSW, was director of the Headquarters Counseling Center in Lawrence, Kan., from 1979 to 2013. The center became part of the first national suicide prevention hotline network, the National Hopeline Network, 1-800-SUICIDE, in 2001, and then became part of the National Suicide Prevention Lifeline, 1-800-274-TALK (8255), when that network began in January 2005.

“The types of programs and agencies which are part of NSPL vary greatly. The accreditation that allows them to be part of the NSPL network also varies. Some centers are staffed totally by licensed mental health therapists, while others might include trained volunteers and paid counselors who have no professional degree or licensure. Service may be delivered by phone, as well as in person, by text, and by live chat. In person might be on site or through mobile crisis outreach. Some centers are part of other organizations, while others are free-standing, and some serve entire states, while others serve geographically smaller regions,” Ms. Epstein explained in a series of e-mails. She noted that some centers assess and refer, while others, like Grassroots, are able to provide more counseling.

“So if it sounds like I’m saying there is little consistency between centers, yes, that is my experience. But the centers all bring strong commitment to preventing suicide.”

Ms. Epstein continued to discuss the power of the work done with hotline callers.

“The really helpful counseling comes from the heart, from connecting to people with caring and respect and patience, and using our skills in helping them stay safer through the crisis and then, when needed, to stay safer in the long run. It takes a lot of bravery from the people letting us help. And it takes a lot of creativity and flexibility in coming up together with realistic plans to support safety.”

I was curious about the patient response, and I found that was mixed. It was also notable that different patients found different forms of communication to be helpful.

A woman who identified herself only as “Virginia Woolf” wrote, “I have contacted the Samaritans on the jo@samaritans.org line because I could write to them via e-mail. I don’t like phones and I also know too many of the counselors on the local crisis line. Each time I was definitely close to suicide. I was in despair and I had the means at hand. I think what stopped me was knowing they would reply. They always did, within a few hours, but waiting for their reply kept me safe.”

Not every response was as positive.

One writer noted, “It was not a productive, supportive, or empathetic person. I felt like she was arrogant, judgmental, and didn’t really care about why I was calling.” The same writer, however, was able to find solace elsewhere. “I have texted CrisisChat and it was an excellent chat and I did feel better.”

Finally, Ms. DeChirico sent me information about the call volume from our local NPSL center in Columbia. From July 1, 2013, to July 31, 2014, the Lifeline received an average of 134 calls per month. December had the highest number of calls, with 163, while August had the lowest with 118. September, February, and April all had 120 calls or fewer.

Robin Williams died on Aug. 11, 2014, and the center received 200 calls in August – a 49% increase over the average volume. Hopefully, we’ll end up seeing a decline in suicide in the months following Mr. Williams’ tragic death.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

National Suicide Prevention Day fell on Sept. 10 this year, surrounded by National Suicide Prevention Week Sept. 8-14. The conversation, as I’m sure everyone noticed, was focused on the suicide of actor Robin Williams. As we move out a few weeks, my patients – especially those who have contemplated ending their own lives – continue to talk about this tragic loss.

The fear is that the suicide of a celebrity will lead to an increase in the suicide rate in the general public – copycat suicides, if you will. In the month after Marilyn Monroe died of an overdose in 1962, the suicide rate rose by more than 10%. On the other hand, the death of a celebrity may lead to a decrease in the suicide rate, as happened after Kurt Cobain’s death from a self-inflicted gunshot wound in 1994. In the period after Cobain’s death, an effort was made to publicize resources for those who need help. The suicide rate dropped, while calls to hotlines rose.

After Robin Williams’ death, my own social media feeds were full of ads for the National Suicide Prevention Lifeline (NSPL), a hotline with the number 1-800-273-TALK. There are other hotlines, but this was the one I saw most. I wanted to learn about suicide hotlines, so I did a few things: I asked readers of our Shrink Rap blog to tell me about their experiences, and I called the hotline myself to see if I could learn about the structure of the organization, what resources they had to offer a distraught caller, and whether there had been a change in the number of calls they’d received in the time following Mr. Williams’ death.

I called from my cell phone, which is registered in Maryland, while sitting in my home in Baltimore City. The call was routed to Grassroots Crisis Intervention Center in Columbia, Md. Google Maps tells me the center is 25 miles from my house, and it would take me 32 minutes to drive there. In addition to being part of a network of 160 hotline centers across the country, Grassroots has a walk-in crisis center and a mobile treatment center, and is adjacent to a homeless shelter.

“Most of the people who call the National Suicide Prevention Lifeline are suicidal,” said Nicole DeChirico, director of crisis intervention services for Grassroots. “There is a gradation in suicidal thinking, but about 90% of our callers are considering it.”

“We first form rapport, and then we try to quickly assess if an attempt has already been made, and if they are in any danger. We use the assessment of suicidality that is put out by the NSPL. It’s a structured template that is used as a guideline.”

Ms. DeChirico noted that the people who man the hotlines have bachelor’s or master’s degrees – often in psychology, social work, counseling, or education. If feasible, a Safety Planning Intervention is implemented, based on the work of Barbara Stanley, Ph.D., at Columbia University in New York.

“We talk to people about what they need to do to feel safe. If they allow it, we set up a follow-up call. Of the total number of people who have attempted suicide once in the past and lived, 90%-96% never go on to attempt suicide again,” Ms. DeChirico noted. Suicide is a time-limited acute crisis.”

The Grassroots team can see patients on site while they wait for appointments with an outpatient clinician, and can send a mobile crisis team to those who need it if they are in the county served by the organization. I wondered if all 160 agencies that received calls from the NSPL could also provide crisis services.

Marcia Epstein, LMSW, was director of the Headquarters Counseling Center in Lawrence, Kan., from 1979 to 2013. The center became part of the first national suicide prevention hotline network, the National Hopeline Network, 1-800-SUICIDE, in 2001, and then became part of the National Suicide Prevention Lifeline, 1-800-274-TALK (8255), when that network began in January 2005.

“The types of programs and agencies which are part of NSPL vary greatly. The accreditation that allows them to be part of the NSPL network also varies. Some centers are staffed totally by licensed mental health therapists, while others might include trained volunteers and paid counselors who have no professional degree or licensure. Service may be delivered by phone, as well as in person, by text, and by live chat. In person might be on site or through mobile crisis outreach. Some centers are part of other organizations, while others are free-standing, and some serve entire states, while others serve geographically smaller regions,” Ms. Epstein explained in a series of e-mails. She noted that some centers assess and refer, while others, like Grassroots, are able to provide more counseling.

“So if it sounds like I’m saying there is little consistency between centers, yes, that is my experience. But the centers all bring strong commitment to preventing suicide.”

Ms. Epstein continued to discuss the power of the work done with hotline callers.

“The really helpful counseling comes from the heart, from connecting to people with caring and respect and patience, and using our skills in helping them stay safer through the crisis and then, when needed, to stay safer in the long run. It takes a lot of bravery from the people letting us help. And it takes a lot of creativity and flexibility in coming up together with realistic plans to support safety.”

I was curious about the patient response, and I found that was mixed. It was also notable that different patients found different forms of communication to be helpful.

A woman who identified herself only as “Virginia Woolf” wrote, “I have contacted the Samaritans on the jo@samaritans.org line because I could write to them via e-mail. I don’t like phones and I also know too many of the counselors on the local crisis line. Each time I was definitely close to suicide. I was in despair and I had the means at hand. I think what stopped me was knowing they would reply. They always did, within a few hours, but waiting for their reply kept me safe.”

Not every response was as positive.

One writer noted, “It was not a productive, supportive, or empathetic person. I felt like she was arrogant, judgmental, and didn’t really care about why I was calling.” The same writer, however, was able to find solace elsewhere. “I have texted CrisisChat and it was an excellent chat and I did feel better.”

Finally, Ms. DeChirico sent me information about the call volume from our local NPSL center in Columbia. From July 1, 2013, to July 31, 2014, the Lifeline received an average of 134 calls per month. December had the highest number of calls, with 163, while August had the lowest with 118. September, February, and April all had 120 calls or fewer.

Robin Williams died on Aug. 11, 2014, and the center received 200 calls in August – a 49% increase over the average volume. Hopefully, we’ll end up seeing a decline in suicide in the months following Mr. Williams’ tragic death.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

National Suicide Prevention Day fell on Sept. 10 this year, surrounded by National Suicide Prevention Week Sept. 8-14. The conversation, as I’m sure everyone noticed, was focused on the suicide of actor Robin Williams. As we move out a few weeks, my patients – especially those who have contemplated ending their own lives – continue to talk about this tragic loss.

The fear is that the suicide of a celebrity will lead to an increase in the suicide rate in the general public – copycat suicides, if you will. In the month after Marilyn Monroe died of an overdose in 1962, the suicide rate rose by more than 10%. On the other hand, the death of a celebrity may lead to a decrease in the suicide rate, as happened after Kurt Cobain’s death from a self-inflicted gunshot wound in 1994. In the period after Cobain’s death, an effort was made to publicize resources for those who need help. The suicide rate dropped, while calls to hotlines rose.

After Robin Williams’ death, my own social media feeds were full of ads for the National Suicide Prevention Lifeline (NSPL), a hotline with the number 1-800-273-TALK. There are other hotlines, but this was the one I saw most. I wanted to learn about suicide hotlines, so I did a few things: I asked readers of our Shrink Rap blog to tell me about their experiences, and I called the hotline myself to see if I could learn about the structure of the organization, what resources they had to offer a distraught caller, and whether there had been a change in the number of calls they’d received in the time following Mr. Williams’ death.

I called from my cell phone, which is registered in Maryland, while sitting in my home in Baltimore City. The call was routed to Grassroots Crisis Intervention Center in Columbia, Md. Google Maps tells me the center is 25 miles from my house, and it would take me 32 minutes to drive there. In addition to being part of a network of 160 hotline centers across the country, Grassroots has a walk-in crisis center and a mobile treatment center, and is adjacent to a homeless shelter.

“Most of the people who call the National Suicide Prevention Lifeline are suicidal,” said Nicole DeChirico, director of crisis intervention services for Grassroots. “There is a gradation in suicidal thinking, but about 90% of our callers are considering it.”

“We first form rapport, and then we try to quickly assess if an attempt has already been made, and if they are in any danger. We use the assessment of suicidality that is put out by the NSPL. It’s a structured template that is used as a guideline.”

Ms. DeChirico noted that the people who man the hotlines have bachelor’s or master’s degrees – often in psychology, social work, counseling, or education. If feasible, a Safety Planning Intervention is implemented, based on the work of Barbara Stanley, Ph.D., at Columbia University in New York.

“We talk to people about what they need to do to feel safe. If they allow it, we set up a follow-up call. Of the total number of people who have attempted suicide once in the past and lived, 90%-96% never go on to attempt suicide again,” Ms. DeChirico noted. Suicide is a time-limited acute crisis.”

The Grassroots team can see patients on site while they wait for appointments with an outpatient clinician, and can send a mobile crisis team to those who need it if they are in the county served by the organization. I wondered if all 160 agencies that received calls from the NSPL could also provide crisis services.

Marcia Epstein, LMSW, was director of the Headquarters Counseling Center in Lawrence, Kan., from 1979 to 2013. The center became part of the first national suicide prevention hotline network, the National Hopeline Network, 1-800-SUICIDE, in 2001, and then became part of the National Suicide Prevention Lifeline, 1-800-274-TALK (8255), when that network began in January 2005.

“The types of programs and agencies which are part of NSPL vary greatly. The accreditation that allows them to be part of the NSPL network also varies. Some centers are staffed totally by licensed mental health therapists, while others might include trained volunteers and paid counselors who have no professional degree or licensure. Service may be delivered by phone, as well as in person, by text, and by live chat. In person might be on site or through mobile crisis outreach. Some centers are part of other organizations, while others are free-standing, and some serve entire states, while others serve geographically smaller regions,” Ms. Epstein explained in a series of e-mails. She noted that some centers assess and refer, while others, like Grassroots, are able to provide more counseling.

“So if it sounds like I’m saying there is little consistency between centers, yes, that is my experience. But the centers all bring strong commitment to preventing suicide.”

Ms. Epstein continued to discuss the power of the work done with hotline callers.

“The really helpful counseling comes from the heart, from connecting to people with caring and respect and patience, and using our skills in helping them stay safer through the crisis and then, when needed, to stay safer in the long run. It takes a lot of bravery from the people letting us help. And it takes a lot of creativity and flexibility in coming up together with realistic plans to support safety.”

I was curious about the patient response, and I found that was mixed. It was also notable that different patients found different forms of communication to be helpful.

A woman who identified herself only as “Virginia Woolf” wrote, “I have contacted the Samaritans on the jo@samaritans.org line because I could write to them via e-mail. I don’t like phones and I also know too many of the counselors on the local crisis line. Each time I was definitely close to suicide. I was in despair and I had the means at hand. I think what stopped me was knowing they would reply. They always did, within a few hours, but waiting for their reply kept me safe.”

Not every response was as positive.

One writer noted, “It was not a productive, supportive, or empathetic person. I felt like she was arrogant, judgmental, and didn’t really care about why I was calling.” The same writer, however, was able to find solace elsewhere. “I have texted CrisisChat and it was an excellent chat and I did feel better.”

Finally, Ms. DeChirico sent me information about the call volume from our local NPSL center in Columbia. From July 1, 2013, to July 31, 2014, the Lifeline received an average of 134 calls per month. December had the highest number of calls, with 163, while August had the lowest with 118. September, February, and April all had 120 calls or fewer.

Robin Williams died on Aug. 11, 2014, and the center received 200 calls in August – a 49% increase over the average volume. Hopefully, we’ll end up seeing a decline in suicide in the months following Mr. Williams’ tragic death.

Dr. Miller is a coauthor of “Shrink Rap: Three Psychiatrists Explain Their Work” (Baltimore: Johns Hopkins University Press, 2011).

Three generations

of women in a family

By studying 3 generations of a family plagued by blood disorders, researchers discovered a genetic mutation that causes aplastic anemia.

The team performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

The mutation disrupts the interactions between telomeres and telomerase, which causes blood cells to die and results in aplastic anemia.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said Hakon Hakonarson, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Hakonarson and his colleagues described this research in Blood.

The team studied an Australian family with aplastic anemia and other hematopoietic disorders, including leukemia. Whole-exome sequencing of the family’s DNA revealed an inherited mutation on the ACD gene.

The mutation is an amino acid deletion in the TEL patch of TPP1 (ΔK170). All of the family members with this mutation had short telomeres, and those with wild-type TPP1 did not.

The researchers introduced TPP1 with the ΔK170 mutation into 293T cells and found the protein could localize to telomeres but failed to recruit telomerase. The team said this indicates a causal relationship between the mutation and bone marrow disorders.

Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list and is the first time the gene has been shown to have a disease-causing role.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” Dr Hakonarson said. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

Three generations

of women in a family

By studying 3 generations of a family plagued by blood disorders, researchers discovered a genetic mutation that causes aplastic anemia.

The team performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

The mutation disrupts the interactions between telomeres and telomerase, which causes blood cells to die and results in aplastic anemia.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said Hakon Hakonarson, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Hakonarson and his colleagues described this research in Blood.

The team studied an Australian family with aplastic anemia and other hematopoietic disorders, including leukemia. Whole-exome sequencing of the family’s DNA revealed an inherited mutation on the ACD gene.

The mutation is an amino acid deletion in the TEL patch of TPP1 (ΔK170). All of the family members with this mutation had short telomeres, and those with wild-type TPP1 did not.

The researchers introduced TPP1 with the ΔK170 mutation into 293T cells and found the protein could localize to telomeres but failed to recruit telomerase. The team said this indicates a causal relationship between the mutation and bone marrow disorders.

Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list and is the first time the gene has been shown to have a disease-causing role.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” Dr Hakonarson said. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

Three generations

of women in a family

By studying 3 generations of a family plagued by blood disorders, researchers discovered a genetic mutation that causes aplastic anemia.

The team performed whole-exome sequencing on DNA from the families and identified an inherited mutation on the ACD gene, which codes for the telomere-binding protein TPP1.

The mutation disrupts the interactions between telomeres and telomerase, which causes blood cells to die and results in aplastic anemia.

“Identifying this causal defect may help suggest future molecular-based treatments that bypass the gene defect and restore blood cell production,” said Hakon Hakonarson, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

Dr Hakonarson and his colleagues described this research in Blood.

The team studied an Australian family with aplastic anemia and other hematopoietic disorders, including leukemia. Whole-exome sequencing of the family’s DNA revealed an inherited mutation on the ACD gene.

The mutation is an amino acid deletion in the TEL patch of TPP1 (ΔK170). All of the family members with this mutation had short telomeres, and those with wild-type TPP1 did not.

The researchers introduced TPP1 with the ΔK170 mutation into 293T cells and found the protein could localize to telomeres but failed to recruit telomerase. The team said this indicates a causal relationship between the mutation and bone marrow disorders.

Without access to telomerase to help maintain telomeres, blood cells lose their structural integrity and die, resulting in bone marrow failure and aplastic anemia.

Nine other genes were previously found to play a role in bone marrow failure disorders. The current study adds ACD to the list and is the first time the gene has been shown to have a disease-causing role.

“This improved understanding of the underlying molecular mechanisms may suggest new approaches to treating disorders such as aplastic anemia,” Dr Hakonarson said. “For instance, investigators may identify other avenues for recruiting telomerase to telomeres to restore its protective function.”

According to the DoD, 300,707 U.S. service members were diagnosed with a traumatic brain injury (TBI) between 2000 and the first quarter of 2014. Of those, 82% had mild TBI (mTBI), also known as a concussion. Usually, a patient recovers from concussion relatively quickly—in days to weeks. But some patients, especially those with preexisting and concomitant conditions, have persistent symptoms that interfere with daily life. The most common of these symptoms are sleep disturbances, usually insomnia, which is a critical issue, given that sleep is so important to the brain’s—and the rest of the body’s—ability to heal. Poor sleep also exacerbates other symptoms, such as pain and irritability, has a negative impact on cognition, and may partially mediate the development of posttraumatic stress disorder or depression.

The Defense and Veterans Brain Injury Center (DVBIC) has released a new clinical recommendation and support tools to help clinicians identify and treat post-TBI sleep disturbances. The suite includes Management of Sleep Disturbances Following Concussion/Mild Traumatic Brain Injury: Guidance for Primary Care Management in Deployed and Non-Deployed Settings, a companion clinical support tool, and a fact sheet for patients. The clinical recommendation (CR) and companion tool are based on a review of current literature and expert contributions from the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, in collaboration with clinical subject matter experts.

The CR strongly advises that all patients with concussion be screened for a sleep disorder. The key question to ask during the patient interview is “Are you experiencing frequent difficulty in falling or staying asleep, excessive daytime sleepiness, or unusual events during sleep?”

The DVBIC Clinical Affairs Officer PHS Capt. Cynthia Spells says “the initial step in the diagnosis of a sleep disorder includes a focused sleep assessment.” The clinical interview should include the “3 Ps”: predisposing, precipitating, and perpetuating factors. Predisposing factors include excessive weight, older age, and medications. Precipitating factors include concussion, deployment, and acute stress. Perpetuating factors include excessive use of caffeine or other stimulants, time zone changes, and familial stress. Noting that comorbid conditions are common with sleep disorders, the CR notes an anxiety disorder postinjury is a more significant predictor of sleep disruption than is pain, other comorbid conditions, or the adverse effects of medication.

A guide for primary care providers (PCPs) in addition to giving an overview of the suite and how to use the components provides insight into the research and science behind managing TBI-related sleep disturbances. The clinical support tool is an algorithm for PCPs to use in assessing sleep disturbances, a step-by-step process to determine the level of care required. The tool is offered as a pocket-sized reference card and can be downloaded. (Health care providers can also take a self-guided course in identifying and treating mTBI at http://www.brainlinemilitary.org.)

According to the CR, nonpharmacologic measures are the first-line treatment for post-TBI sleep problems. These include teaching patients good sleep hygiene and stimulus control; that is, doing as much as possible to physically and environmentally promote sleep. (See App Corner) The patient fact sheet gives tips on getting a healthy night’ s sleep, such as avoiding naps, avoiding alcohol close to bedtime, and getting exposure to natural light as much as possible.

The CR and other components are available at https://dvbic.dcoe.mil/resources/management-sleep-disturbances.

According to the DoD, 300,707 U.S. service members were diagnosed with a traumatic brain injury (TBI) between 2000 and the first quarter of 2014. Of those, 82% had mild TBI (mTBI), also known as a concussion. Usually, a patient recovers from concussion relatively quickly—in days to weeks. But some patients, especially those with preexisting and concomitant conditions, have persistent symptoms that interfere with daily life. The most common of these symptoms are sleep disturbances, usually insomnia, which is a critical issue, given that sleep is so important to the brain’s—and the rest of the body’s—ability to heal. Poor sleep also exacerbates other symptoms, such as pain and irritability, has a negative impact on cognition, and may partially mediate the development of posttraumatic stress disorder or depression.

The Defense and Veterans Brain Injury Center (DVBIC) has released a new clinical recommendation and support tools to help clinicians identify and treat post-TBI sleep disturbances. The suite includes Management of Sleep Disturbances Following Concussion/Mild Traumatic Brain Injury: Guidance for Primary Care Management in Deployed and Non-Deployed Settings, a companion clinical support tool, and a fact sheet for patients. The clinical recommendation (CR) and companion tool are based on a review of current literature and expert contributions from the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, in collaboration with clinical subject matter experts.

The CR strongly advises that all patients with concussion be screened for a sleep disorder. The key question to ask during the patient interview is “Are you experiencing frequent difficulty in falling or staying asleep, excessive daytime sleepiness, or unusual events during sleep?”

The DVBIC Clinical Affairs Officer PHS Capt. Cynthia Spells says “the initial step in the diagnosis of a sleep disorder includes a focused sleep assessment.” The clinical interview should include the “3 Ps”: predisposing, precipitating, and perpetuating factors. Predisposing factors include excessive weight, older age, and medications. Precipitating factors include concussion, deployment, and acute stress. Perpetuating factors include excessive use of caffeine or other stimulants, time zone changes, and familial stress. Noting that comorbid conditions are common with sleep disorders, the CR notes an anxiety disorder postinjury is a more significant predictor of sleep disruption than is pain, other comorbid conditions, or the adverse effects of medication.

A guide for primary care providers (PCPs) in addition to giving an overview of the suite and how to use the components provides insight into the research and science behind managing TBI-related sleep disturbances. The clinical support tool is an algorithm for PCPs to use in assessing sleep disturbances, a step-by-step process to determine the level of care required. The tool is offered as a pocket-sized reference card and can be downloaded. (Health care providers can also take a self-guided course in identifying and treating mTBI at http://www.brainlinemilitary.org.)

According to the CR, nonpharmacologic measures are the first-line treatment for post-TBI sleep problems. These include teaching patients good sleep hygiene and stimulus control; that is, doing as much as possible to physically and environmentally promote sleep. (See App Corner) The patient fact sheet gives tips on getting a healthy night’ s sleep, such as avoiding naps, avoiding alcohol close to bedtime, and getting exposure to natural light as much as possible.

The CR and other components are available at https://dvbic.dcoe.mil/resources/management-sleep-disturbances.

According to the DoD, 300,707 U.S. service members were diagnosed with a traumatic brain injury (TBI) between 2000 and the first quarter of 2014. Of those, 82% had mild TBI (mTBI), also known as a concussion. Usually, a patient recovers from concussion relatively quickly—in days to weeks. But some patients, especially those with preexisting and concomitant conditions, have persistent symptoms that interfere with daily life. The most common of these symptoms are sleep disturbances, usually insomnia, which is a critical issue, given that sleep is so important to the brain’s—and the rest of the body’s—ability to heal. Poor sleep also exacerbates other symptoms, such as pain and irritability, has a negative impact on cognition, and may partially mediate the development of posttraumatic stress disorder or depression.

The Defense and Veterans Brain Injury Center (DVBIC) has released a new clinical recommendation and support tools to help clinicians identify and treat post-TBI sleep disturbances. The suite includes Management of Sleep Disturbances Following Concussion/Mild Traumatic Brain Injury: Guidance for Primary Care Management in Deployed and Non-Deployed Settings, a companion clinical support tool, and a fact sheet for patients. The clinical recommendation (CR) and companion tool are based on a review of current literature and expert contributions from the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, in collaboration with clinical subject matter experts.

The CR strongly advises that all patients with concussion be screened for a sleep disorder. The key question to ask during the patient interview is “Are you experiencing frequent difficulty in falling or staying asleep, excessive daytime sleepiness, or unusual events during sleep?”

The DVBIC Clinical Affairs Officer PHS Capt. Cynthia Spells says “the initial step in the diagnosis of a sleep disorder includes a focused sleep assessment.” The clinical interview should include the “3 Ps”: predisposing, precipitating, and perpetuating factors. Predisposing factors include excessive weight, older age, and medications. Precipitating factors include concussion, deployment, and acute stress. Perpetuating factors include excessive use of caffeine or other stimulants, time zone changes, and familial stress. Noting that comorbid conditions are common with sleep disorders, the CR notes an anxiety disorder postinjury is a more significant predictor of sleep disruption than is pain, other comorbid conditions, or the adverse effects of medication.

A guide for primary care providers (PCPs) in addition to giving an overview of the suite and how to use the components provides insight into the research and science behind managing TBI-related sleep disturbances. The clinical support tool is an algorithm for PCPs to use in assessing sleep disturbances, a step-by-step process to determine the level of care required. The tool is offered as a pocket-sized reference card and can be downloaded. (Health care providers can also take a self-guided course in identifying and treating mTBI at http://www.brainlinemilitary.org.)

According to the CR, nonpharmacologic measures are the first-line treatment for post-TBI sleep problems. These include teaching patients good sleep hygiene and stimulus control; that is, doing as much as possible to physically and environmentally promote sleep. (See App Corner) The patient fact sheet gives tips on getting a healthy night’ s sleep, such as avoiding naps, avoiding alcohol close to bedtime, and getting exposure to natural light as much as possible.

The CR and other components are available at https://dvbic.dcoe.mil/resources/management-sleep-disturbances.

AML in the bone marrow

PHILADELPHIA—Super-enhancer profiling can unearth biomarkers and therapeutic targets for acute myeloid leukemia (AML), according to research presented at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

Researchers used high-throughput ChIP sequencing to identify super-enhancer domains in a cohort of AML patients.

And this revealed both known and previously unknown genes that are important for AML disease biology.

Eric Olson, PhD, and his colleagues from Syros Pharmaceuticals in Watertown, Massachusetts, presented this research during one of the meeting’s poster sessions.

The investigators explained that super-enhancers are a class of densely clustered cis-regulatory elements that are key to initiating and maintaining cell-type-specific gene expression in cancer and other settings. Tumor cells acquire super-enhancers at key oncogenes and at genes that participate in the acquisition of hallmark capabilities in cancer.

So the researchers set out to identify and characterize super-enhancer domains in a cohort of AML patients.

The team collected primary AML samples and performed chromatin fragmentation, chromatin immunoprecipitation, and DNA purification and sequencing.

They then mapped enhancer regions and characterized enhancer profiles. This revealed AML-specific super-enhancers and associated genes.

For example, in one patient, the investigators identified 392 AML-specific super-enhancers, which were associated with 11 genes important for AML disease biology: HOXA7, LMO2, HLX, MYADM, ETV6, AFF1, RUNX1, GFI1, SPI1, MEIS1, and MYB.

In another patient, the team identified 279 AML-specific super-enhancers that were associated with 9 genes: MLLT10, AKT3, FLT3, ETV6, KLF13, RELA, FOSB, BMI1, and RUNX1.

The researchers said these findings suggest that super-enhancer profiling provides a new option for identifying biomarkers and therapeutic targets in AML and other malignancies.

“Syros’s gene control platform can systematically and efficiently identify known and previously unrecognized tumor biomarkers and cancer dependencies directly from patient tissue,” Dr Olson said. “Our data demonstrate unique gene control elements in AML patient subsets that hold promise in the classification and treatment of AML.”

AML in the bone marrow

PHILADELPHIA—Super-enhancer profiling can unearth biomarkers and therapeutic targets for acute myeloid leukemia (AML), according to research presented at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

Researchers used high-throughput ChIP sequencing to identify super-enhancer domains in a cohort of AML patients.

And this revealed both known and previously unknown genes that are important for AML disease biology.

Eric Olson, PhD, and his colleagues from Syros Pharmaceuticals in Watertown, Massachusetts, presented this research during one of the meeting’s poster sessions.

The investigators explained that super-enhancers are a class of densely clustered cis-regulatory elements that are key to initiating and maintaining cell-type-specific gene expression in cancer and other settings. Tumor cells acquire super-enhancers at key oncogenes and at genes that participate in the acquisition of hallmark capabilities in cancer.

So the researchers set out to identify and characterize super-enhancer domains in a cohort of AML patients.

The team collected primary AML samples and performed chromatin fragmentation, chromatin immunoprecipitation, and DNA purification and sequencing.

They then mapped enhancer regions and characterized enhancer profiles. This revealed AML-specific super-enhancers and associated genes.

For example, in one patient, the investigators identified 392 AML-specific super-enhancers, which were associated with 11 genes important for AML disease biology: HOXA7, LMO2, HLX, MYADM, ETV6, AFF1, RUNX1, GFI1, SPI1, MEIS1, and MYB.

In another patient, the team identified 279 AML-specific super-enhancers that were associated with 9 genes: MLLT10, AKT3, FLT3, ETV6, KLF13, RELA, FOSB, BMI1, and RUNX1.

The researchers said these findings suggest that super-enhancer profiling provides a new option for identifying biomarkers and therapeutic targets in AML and other malignancies.

“Syros’s gene control platform can systematically and efficiently identify known and previously unrecognized tumor biomarkers and cancer dependencies directly from patient tissue,” Dr Olson said. “Our data demonstrate unique gene control elements in AML patient subsets that hold promise in the classification and treatment of AML.”

AML in the bone marrow

PHILADELPHIA—Super-enhancer profiling can unearth biomarkers and therapeutic targets for acute myeloid leukemia (AML), according to research presented at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.

Researchers used high-throughput ChIP sequencing to identify super-enhancer domains in a cohort of AML patients.

And this revealed both known and previously unknown genes that are important for AML disease biology.

Eric Olson, PhD, and his colleagues from Syros Pharmaceuticals in Watertown, Massachusetts, presented this research during one of the meeting’s poster sessions.

The investigators explained that super-enhancers are a class of densely clustered cis-regulatory elements that are key to initiating and maintaining cell-type-specific gene expression in cancer and other settings. Tumor cells acquire super-enhancers at key oncogenes and at genes that participate in the acquisition of hallmark capabilities in cancer.

So the researchers set out to identify and characterize super-enhancer domains in a cohort of AML patients.

The team collected primary AML samples and performed chromatin fragmentation, chromatin immunoprecipitation, and DNA purification and sequencing.

They then mapped enhancer regions and characterized enhancer profiles. This revealed AML-specific super-enhancers and associated genes.

For example, in one patient, the investigators identified 392 AML-specific super-enhancers, which were associated with 11 genes important for AML disease biology: HOXA7, LMO2, HLX, MYADM, ETV6, AFF1, RUNX1, GFI1, SPI1, MEIS1, and MYB.

In another patient, the team identified 279 AML-specific super-enhancers that were associated with 9 genes: MLLT10, AKT3, FLT3, ETV6, KLF13, RELA, FOSB, BMI1, and RUNX1.

The researchers said these findings suggest that super-enhancer profiling provides a new option for identifying biomarkers and therapeutic targets in AML and other malignancies.

“Syros’s gene control platform can systematically and efficiently identify known and previously unrecognized tumor biomarkers and cancer dependencies directly from patient tissue,” Dr Olson said. “Our data demonstrate unique gene control elements in AML patient subsets that hold promise in the classification and treatment of AML.”

Pricked finger

The UK’s National Institute for Health and Care Excellence (NICE) has published a guidance recommending 2 technologies that enable patients on long-term anticoagulant therapy to self-monitor their clotting time.

The guidance supports use of the Coaguchek XS system (Roche Diagnostics) and the InRatio2 PT/INR Monitor (Alere) as options for some adults with atrial

fibrillation or heart valve disease who are on long-term anticoagulant therapy.

“The evidence shows that greater use of self-monitoring offers clinical and patient benefit and, over time, is likely to result in reductions in heart attacks and strokes caused by blood clots,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“Because self-monitoring provides almost instant results, self-monitoring can reduce anxiety, provide a sense of control for the patient, and remove the need to frequently attend clinics or hospitals.”

About the Coaguchek XS system

The Coaguchek XS system (Roche Diagnostics) consists of a meter and specifically designed test strips that can analyze a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time (PT) and the international normalized ratio (INR).

A code chip, which contains calibration data and the expiration date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted, and the blood sample is applied.

The test result is displayed approximately 1 minute after application of the sample, and the device automatically stores the result in its memory. The user is guided through the process by on-screen graphical instructions.

About the InRatio2 PT/INR Monitor

The INRatio2 PT/INR monitor (Alere) does a modified version of the 1-stage PT test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process.

The system consists of a monitor and disposable test strips. The monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports PT and INR results.

Instructions and test results are displayed on an LCD. The monitor can store test results so that past results can be reviewed.

Pricked finger

The UK’s National Institute for Health and Care Excellence (NICE) has published a guidance recommending 2 technologies that enable patients on long-term anticoagulant therapy to self-monitor their clotting time.

The guidance supports use of the Coaguchek XS system (Roche Diagnostics) and the InRatio2 PT/INR Monitor (Alere) as options for some adults with atrial

fibrillation or heart valve disease who are on long-term anticoagulant therapy.

“The evidence shows that greater use of self-monitoring offers clinical and patient benefit and, over time, is likely to result in reductions in heart attacks and strokes caused by blood clots,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“Because self-monitoring provides almost instant results, self-monitoring can reduce anxiety, provide a sense of control for the patient, and remove the need to frequently attend clinics or hospitals.”

About the Coaguchek XS system

The Coaguchek XS system (Roche Diagnostics) consists of a meter and specifically designed test strips that can analyze a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time (PT) and the international normalized ratio (INR).

A code chip, which contains calibration data and the expiration date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted, and the blood sample is applied.

The test result is displayed approximately 1 minute after application of the sample, and the device automatically stores the result in its memory. The user is guided through the process by on-screen graphical instructions.

About the InRatio2 PT/INR Monitor

The INRatio2 PT/INR monitor (Alere) does a modified version of the 1-stage PT test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process.

The system consists of a monitor and disposable test strips. The monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports PT and INR results.

Instructions and test results are displayed on an LCD. The monitor can store test results so that past results can be reviewed.

Pricked finger

The UK’s National Institute for Health and Care Excellence (NICE) has published a guidance recommending 2 technologies that enable patients on long-term anticoagulant therapy to self-monitor their clotting time.

The guidance supports use of the Coaguchek XS system (Roche Diagnostics) and the InRatio2 PT/INR Monitor (Alere) as options for some adults with atrial

fibrillation or heart valve disease who are on long-term anticoagulant therapy.

“The evidence shows that greater use of self-monitoring offers clinical and patient benefit and, over time, is likely to result in reductions in heart attacks and strokes caused by blood clots,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“Because self-monitoring provides almost instant results, self-monitoring can reduce anxiety, provide a sense of control for the patient, and remove the need to frequently attend clinics or hospitals.”

About the Coaguchek XS system

The Coaguchek XS system (Roche Diagnostics) consists of a meter and specifically designed test strips that can analyze a blood sample (fresh capillary blood or fresh untreated whole venous blood) and calculate the prothrombin time (PT) and the international normalized ratio (INR).

A code chip, which contains calibration data and the expiration date of the test strips, is inserted into the meter before it is switched on. Once the device is switched on, a test strip is inserted, and the blood sample is applied.

The test result is displayed approximately 1 minute after application of the sample, and the device automatically stores the result in its memory. The user is guided through the process by on-screen graphical instructions.

About the InRatio2 PT/INR Monitor

The INRatio2 PT/INR monitor (Alere) does a modified version of the 1-stage PT test using a recombinant human thromboplastin reagent. The clot formed in the reaction is detected by the change in the electrical impedance of the sample during the coagulation process.

The system consists of a monitor and disposable test strips. The monitor provides a user interface, heats the test strip to the appropriate reaction temperature, measures the impedance of blood samples, and calculates and reports PT and INR results.

Instructions and test results are displayed on an LCD. The monitor can store test results so that past results can be reviewed.