Leukemia, Myelodysplasia, Transplantation

Scientist in the lab

Photo by Darren Baker

By tracking the evolution of Abl and Src, investigators have made discoveries that may aid the design of highly specific cancer drugs.

Abl and Src are 2 nearly identical protein kinases with a predilection to cause cancer in humans, mainly chronic myeloid leukemia and colon cancer.

The proteins are separated by 146 amino acids and one big difference: Abl is susceptible to treatment with the tyrosine kinase inhibitor imatinib (Gleevec), but Src is not.

Dorothee Kern, PhD, of Brandeis University in Waltham, Massachusetts, and her colleagues traced the journey of these 2 proteins over 1 billion years of evolution, pinpointing the exact evolutionary shifts that caused imatinib to bind well with one protein and poorly with the other.

This new approach to researching enzymes and their binding sites may have a major impact on the development of cancer drugs, the investigators said.

They published their findings in Science.

To determine why imatinib binds with Abl but not Src, Dr Kern and her colleagues turned back the evolutionary clock 1 billion years.

This revealed Abl and Src’s common ancestor, a primitive protein in yeast the team dubbed “ANC-AS.” They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids, and we were looking for the handful that dictate Gleevec specificity,” Dr Kern said. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles, and catalysis processes—creating Abl and Src.

By following this progression, while testing the proteins’ affinity to imatinib along the way, the investigators were able to whittle down the 146 different amino acids to 15 that are responsible for imatinib specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium—a process in which the protein transitions between 2 structures. The main difference between Abl and Src, when it comes to binding with imatinib, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why imatinib works on Abl—and doesn’t work on Src—scientists have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity has opened the door wider to designing good drugs,” Dr Kern said. “Our results pave the way for a different approach to rational drug design.”

Scientist in the lab

Photo by Darren Baker

By tracking the evolution of Abl and Src, investigators have made discoveries that may aid the design of highly specific cancer drugs.

Abl and Src are 2 nearly identical protein kinases with a predilection to cause cancer in humans, mainly chronic myeloid leukemia and colon cancer.

The proteins are separated by 146 amino acids and one big difference: Abl is susceptible to treatment with the tyrosine kinase inhibitor imatinib (Gleevec), but Src is not.

Dorothee Kern, PhD, of Brandeis University in Waltham, Massachusetts, and her colleagues traced the journey of these 2 proteins over 1 billion years of evolution, pinpointing the exact evolutionary shifts that caused imatinib to bind well with one protein and poorly with the other.

This new approach to researching enzymes and their binding sites may have a major impact on the development of cancer drugs, the investigators said.

They published their findings in Science.

To determine why imatinib binds with Abl but not Src, Dr Kern and her colleagues turned back the evolutionary clock 1 billion years.

This revealed Abl and Src’s common ancestor, a primitive protein in yeast the team dubbed “ANC-AS.” They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids, and we were looking for the handful that dictate Gleevec specificity,” Dr Kern said. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles, and catalysis processes—creating Abl and Src.

By following this progression, while testing the proteins’ affinity to imatinib along the way, the investigators were able to whittle down the 146 different amino acids to 15 that are responsible for imatinib specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium—a process in which the protein transitions between 2 structures. The main difference between Abl and Src, when it comes to binding with imatinib, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why imatinib works on Abl—and doesn’t work on Src—scientists have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity has opened the door wider to designing good drugs,” Dr Kern said. “Our results pave the way for a different approach to rational drug design.”

Scientist in the lab

Photo by Darren Baker

By tracking the evolution of Abl and Src, investigators have made discoveries that may aid the design of highly specific cancer drugs.

Abl and Src are 2 nearly identical protein kinases with a predilection to cause cancer in humans, mainly chronic myeloid leukemia and colon cancer.

The proteins are separated by 146 amino acids and one big difference: Abl is susceptible to treatment with the tyrosine kinase inhibitor imatinib (Gleevec), but Src is not.

Dorothee Kern, PhD, of Brandeis University in Waltham, Massachusetts, and her colleagues traced the journey of these 2 proteins over 1 billion years of evolution, pinpointing the exact evolutionary shifts that caused imatinib to bind well with one protein and poorly with the other.

This new approach to researching enzymes and their binding sites may have a major impact on the development of cancer drugs, the investigators said.

They published their findings in Science.

To determine why imatinib binds with Abl but not Src, Dr Kern and her colleagues turned back the evolutionary clock 1 billion years.

This revealed Abl and Src’s common ancestor, a primitive protein in yeast the team dubbed “ANC-AS.” They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.

“Src and Abl differ by 146 amino acids, and we were looking for the handful that dictate Gleevec specificity,” Dr Kern said. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”

As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles, and catalysis processes—creating Abl and Src.

By following this progression, while testing the proteins’ affinity to imatinib along the way, the investigators were able to whittle down the 146 different amino acids to 15 that are responsible for imatinib specificity.

These 15 amino acids play a role in Abl’s conformational equilibrium—a process in which the protein transitions between 2 structures. The main difference between Abl and Src, when it comes to binding with imatinib, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.

By understanding how and why imatinib works on Abl—and doesn’t work on Src—scientists have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.

“Understanding the molecular basis for Gleevec specificity has opened the door wider to designing good drugs,” Dr Kern said. “Our results pave the way for a different approach to rational drug design.”

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Preparing HSCs for transplant

Photo by Chad McNeeley

SAN DIEGO—A retrospective study has revealed a few factors that may predict outcomes of allogeneic hematopoietic stem cell transplant (allo-HSCT) in adults with acute lymphoblastic leukemia (ALL).

The study showed that cytogenetics at diagnosis did not impact survival rates, although having high-risk cytogenetics was associated with an increased incidence of relapse in patients who were transplanted in their first complete remission (CR1).

Patients who were not in CR1 at transplant tended to have worse survival and higher relapse rates.

And patients who received a tacrolimus/sirolimus-based regimen as graft-vs-host disease (GVHD) prophylaxis had better survival rates than their peers, but their relapse rates did not differ.

Ibrahim Aldoss, MD, of City of Hope Medical Center in Duarte, California, presented these findings at the 2015 BMT Tandem Meetings as abstract 69.*

Dr Aldoss said there is a lack of data addressing individual ALL-related prognostic factors for transplant outcomes. So he and his colleagues decided to analyze 358 adult ALL patients who received allo-HSCT at the City of Hope from January 2004 through March 2014.

The patients’ median age was 38 (range, 18 to 72), and most patients (91%) had B-cell disease. At diagnosis, 2% of patients had good-risk cytogenetics, 43% had intermediate-risk, and 46% had poor-risk. For 9% of patients, the cytogenetic risk group was unknown.

At transplant, 60% of patients were in CR1, 17% were in CR2, and 23% were in a subsequent CR or had refractory disease.

Most patients received peripheral blood stem cell transplant (86%), 7% of patients received bone marrow, and the same percentage received cord blood. Fifty-four percent of patients had a matched sibling donor, 45% had an unrelated donor, and 1% had a related donor.

Eighty-one percent of patients received myeloablative conditioning, and the same percentage received a tacrolimus/sirolimus-based regimen for GVHD prophylaxis.

The 3-year estimated overall survival (OS) rate was 54%, leukemia-free survival (LFS) was 47%, and the cumulative incidence of relapse (CIR) was 27%. The 1-year non-relapse mortality (NRM) rate was 19%.

In multivariable analyses, disease status at allo-HSCT was an independent predictor of OS, LFS, and CIR. For OS, when the researchers compared patients in CR1 to those in CR2, the hazard ratio (HR) was 1.87 (P<0.01). When patients in CR1 were compared to other patients, the HR was 2.79 (P<0.01).

For LFS, the HRs were 1.69 (P=0.02) for CR1 vs CR2 and 2.94 (P<0.01) for CR1 vs others. And for CIR, the HRs were 2.21 (P<0.01) and 3.55 (P<0.01), respectively.

The analyses also revealed that tacrolimus/sirolimus-based GVHD prophylaxis was an independent predictor of OS, LFS, and NRM. The HRs were 1.58 (P=0.03), 1.5 (P=0.03), and 1.75 (P=0.03), respectively.

“So cytogenetics at diagnosis did not impact overall survival or leukemia-free survival among adult ALL patients who underwent allogeneic stem cell transplantation,” Dr Aldoss said in closing. “However, high-risk cytogenetics was associated with an increased cumulative incidence of relapse in patients transplanted in CR1.”

“Non-CR1 status at the time of transplant adversely affected overall survival, leukemia-free survival, and cumulative incidence of relapse. And a tacrolimus/sirolimus-based GVHD prophylaxis regimen was associated with improved overall survival, leukemia-free survival, and non-relapse mortality but did not influence the cumulative incidence of relapse.”

*Information in the abstract differs from that presented at the meeting.

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of 2 new studies indicate that young adults (ages 18 to 39) who have survived leukemia or lymphoma are more likely to report high distress than older survivors (age 65 and older).

Specifically, 45% of younger survivors reported moderate-to-high distress, whereas only 18% of older survivors reported similarly elevated levels.

In both groups, this distress was not affected by the amount of time since a patient received treatment. Distress was just as likely to be high in survivors who had completed treatment 4 years prior as in survivors who were 3 months out of treatment.

Whitney Jones, PhD, of the University of Colorado Denver, and her colleagues reported these findings in the Journal of Psychosocial Oncology.

In the first study, Dr Jones and her colleagues surveyed 477 cancer survivors, using a widely used measure of distress after trauma and several items from a measure of quality of life in cancer survivors.

These measures allowed the researchers to ask which factors of a cancer survivor’s life after treatment are the best predictors of persistent distress after treatment completion.

And results showed that survivors younger than 40 had the highest prevalence of distress.

Dr Jones explained the effect of age on distress using a framework called the Lifespan Perspective. Because there is an expected social, cultural, and developmental course of a person’s life, an event that is highly disruptive in one lifespan stage may be less disruptive in another.

“For younger survivors, cancer is out of context,” Dr Jones said. “When you’re under 40, you’re finishing your education, entering the workforce, starting a family, and cancer may be interpreted as disruptive and unexpected in that phase.”

“On the other hand, some of our older survivors said things like, ‘Cancer isn’t the most difficult thing I’ve experienced in life.’ And they knew friends and family members who had dealt with similar cancer experiences.”

The study also showed that people who feared recurrence were most likely to report high overall distress levels. And high financial burden due to cancer treatment predicted distress.

In the second study, the researchers used interviews with 51 leukemia and lymphoma survivors to explore the human side of these numbers and better understand the sources of distress as articulated by survivors themselves.

“For example, this was before the Affordable Care Act, and we had one survivor who talked about having only the basic college student insurance when he was diagnosed,” Dr Jones said. “After treatment, he discovered he had substantial medical debt and was uninsurable.”

“It helped to hear survivors talk about their experiences in their own words. To hear them articulate it helped us understand the real struggles behind our data.”

The interviews also helped to explain why distress lingers even years after treatment ends.

“A patient told us that, after lymphoma treatment, her doctor said that it would take 2 years to recover physically and mentally, and that almost all the gains would be in these 2 years,” Dr Jones said.

“She said something like, ‘I was really patient for 2 years, then after those 2 years passed, I didn’t feel any better and realized this is what I was going to be living with.’”

Distress detection and treatment is increasingly being seen as part of the standard of care for cancer patients and post-treatment survivors, the researchers noted.

For example, organizations like the National Comprehensive Cancer Network and the American College of Surgeons Commission on Cancer mandate distress screening and treatment in order to earn accreditation from these institutions.

“Understanding which individuals are most likely to experience elevated distress can be useful in targeting interventions to potential participants,” Dr Jones said.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of 2 new studies indicate that young adults (ages 18 to 39) who have survived leukemia or lymphoma are more likely to report high distress than older survivors (age 65 and older).

Specifically, 45% of younger survivors reported moderate-to-high distress, whereas only 18% of older survivors reported similarly elevated levels.

In both groups, this distress was not affected by the amount of time since a patient received treatment. Distress was just as likely to be high in survivors who had completed treatment 4 years prior as in survivors who were 3 months out of treatment.

Whitney Jones, PhD, of the University of Colorado Denver, and her colleagues reported these findings in the Journal of Psychosocial Oncology.

In the first study, Dr Jones and her colleagues surveyed 477 cancer survivors, using a widely used measure of distress after trauma and several items from a measure of quality of life in cancer survivors.

These measures allowed the researchers to ask which factors of a cancer survivor’s life after treatment are the best predictors of persistent distress after treatment completion.

And results showed that survivors younger than 40 had the highest prevalence of distress.

Dr Jones explained the effect of age on distress using a framework called the Lifespan Perspective. Because there is an expected social, cultural, and developmental course of a person’s life, an event that is highly disruptive in one lifespan stage may be less disruptive in another.

“For younger survivors, cancer is out of context,” Dr Jones said. “When you’re under 40, you’re finishing your education, entering the workforce, starting a family, and cancer may be interpreted as disruptive and unexpected in that phase.”

“On the other hand, some of our older survivors said things like, ‘Cancer isn’t the most difficult thing I’ve experienced in life.’ And they knew friends and family members who had dealt with similar cancer experiences.”

The study also showed that people who feared recurrence were most likely to report high overall distress levels. And high financial burden due to cancer treatment predicted distress.

In the second study, the researchers used interviews with 51 leukemia and lymphoma survivors to explore the human side of these numbers and better understand the sources of distress as articulated by survivors themselves.

“For example, this was before the Affordable Care Act, and we had one survivor who talked about having only the basic college student insurance when he was diagnosed,” Dr Jones said. “After treatment, he discovered he had substantial medical debt and was uninsurable.”

“It helped to hear survivors talk about their experiences in their own words. To hear them articulate it helped us understand the real struggles behind our data.”

The interviews also helped to explain why distress lingers even years after treatment ends.

“A patient told us that, after lymphoma treatment, her doctor said that it would take 2 years to recover physically and mentally, and that almost all the gains would be in these 2 years,” Dr Jones said.

“She said something like, ‘I was really patient for 2 years, then after those 2 years passed, I didn’t feel any better and realized this is what I was going to be living with.’”

Distress detection and treatment is increasingly being seen as part of the standard of care for cancer patients and post-treatment survivors, the researchers noted.

For example, organizations like the National Comprehensive Cancer Network and the American College of Surgeons Commission on Cancer mandate distress screening and treatment in order to earn accreditation from these institutions.

“Understanding which individuals are most likely to experience elevated distress can be useful in targeting interventions to potential participants,” Dr Jones said.

Doctor consults with a cancer

patient and her father

Photo by Rhoda Baer

Results of 2 new studies indicate that young adults (ages 18 to 39) who have survived leukemia or lymphoma are more likely to report high distress than older survivors (age 65 and older).

Specifically, 45% of younger survivors reported moderate-to-high distress, whereas only 18% of older survivors reported similarly elevated levels.

In both groups, this distress was not affected by the amount of time since a patient received treatment. Distress was just as likely to be high in survivors who had completed treatment 4 years prior as in survivors who were 3 months out of treatment.

Whitney Jones, PhD, of the University of Colorado Denver, and her colleagues reported these findings in the Journal of Psychosocial Oncology.

In the first study, Dr Jones and her colleagues surveyed 477 cancer survivors, using a widely used measure of distress after trauma and several items from a measure of quality of life in cancer survivors.

These measures allowed the researchers to ask which factors of a cancer survivor’s life after treatment are the best predictors of persistent distress after treatment completion.

And results showed that survivors younger than 40 had the highest prevalence of distress.

Dr Jones explained the effect of age on distress using a framework called the Lifespan Perspective. Because there is an expected social, cultural, and developmental course of a person’s life, an event that is highly disruptive in one lifespan stage may be less disruptive in another.

“For younger survivors, cancer is out of context,” Dr Jones said. “When you’re under 40, you’re finishing your education, entering the workforce, starting a family, and cancer may be interpreted as disruptive and unexpected in that phase.”

“On the other hand, some of our older survivors said things like, ‘Cancer isn’t the most difficult thing I’ve experienced in life.’ And they knew friends and family members who had dealt with similar cancer experiences.”

The study also showed that people who feared recurrence were most likely to report high overall distress levels. And high financial burden due to cancer treatment predicted distress.

In the second study, the researchers used interviews with 51 leukemia and lymphoma survivors to explore the human side of these numbers and better understand the sources of distress as articulated by survivors themselves.

“For example, this was before the Affordable Care Act, and we had one survivor who talked about having only the basic college student insurance when he was diagnosed,” Dr Jones said. “After treatment, he discovered he had substantial medical debt and was uninsurable.”

“It helped to hear survivors talk about their experiences in their own words. To hear them articulate it helped us understand the real struggles behind our data.”

The interviews also helped to explain why distress lingers even years after treatment ends.

“A patient told us that, after lymphoma treatment, her doctor said that it would take 2 years to recover physically and mentally, and that almost all the gains would be in these 2 years,” Dr Jones said.

“She said something like, ‘I was really patient for 2 years, then after those 2 years passed, I didn’t feel any better and realized this is what I was going to be living with.’”

Distress detection and treatment is increasingly being seen as part of the standard of care for cancer patients and post-treatment survivors, the researchers noted.

For example, organizations like the National Comprehensive Cancer Network and the American College of Surgeons Commission on Cancer mandate distress screening and treatment in order to earn accreditation from these institutions.

“Understanding which individuals are most likely to experience elevated distress can be useful in targeting interventions to potential participants,” Dr Jones said.

Doctor consults with a patient

Photo courtesy of NIH

Although it makes sense that patient requests might drive physicians to practice defensive medicine, new research suggests that may not be the case with cancer patients.

The study, conducted at outpatient oncology centers, showed that patients rarely made clinically inappropriate requests.

Only 1% of more than 5000 patient-clinician encounters resulted in a clinically inappropriate request. And physicians rarely complied with these requests.

Keerthi Gogineni, MD, of the Hospital of the University of Pennsylvania in Philadelphia, and colleagues  reported these findings in JAMA Oncology.

The researchers analyzed interviews with clinicians immediately after they visited with patients to assess whether a patient had made a request, the type of request made, and the clinical appropriateness of it.

The interviews were conducted at outpatient oncology facilities at 3 Philadelphia-area hospitals between October 2013 and June 2014.

The authors evaluated 5050 patient-clinician encounters involving 3624 patients and 60 clinicians. Most of the patients were women, and the most common cancer was hematologic.

Overall, 440 (8.7%) of the encounters included a patient demand or request, such as for imaging studies, treatments, or tests. And physicians complied with 365 (83%) of them.

Of all the patient-clinician encounters, 50 (1%) included a clinically inappropriate request. Clinicians complied with 7 of them. So, in 0.14% of encounters, clinicians ordered a test or treatment based on a clinically inappropriate request.

“At least in oncology, ‘demanding patients’ seem infrequent and may not account for a significant proportion of costs,” the researchers concluded.

In a related editorial, Anthony L. Back, MD, of the Seattle Cancer Care Alliance in Washington, wrote that inappropriate patient demands appear to be “more mythical than real.”

“[W]e have to stop blaming patients for being demanding,” he wrote. “In reality, it is hardly happening. The myth of the demanding patient is more about our own responses and how lackluster communication skills can contribute to difficult situations that stick in our throats and in our memories. And when we have calmed down enough to look up, we see that what is really happening between patients and physicians these days is something quite different.”

“It is possible that what the study by Gogineni et al documents is a point in the evolution of the patient-physician relationship when both sides recognize the complexity of cancer care belies a simple fix. Perhaps this ‘negative’ study is pointing to an important truth: that we need to redirect our attention from the myths that are distracting us.”

Doctor consults with a patient

Photo courtesy of NIH

Although it makes sense that patient requests might drive physicians to practice defensive medicine, new research suggests that may not be the case with cancer patients.

The study, conducted at outpatient oncology centers, showed that patients rarely made clinically inappropriate requests.

Only 1% of more than 5000 patient-clinician encounters resulted in a clinically inappropriate request. And physicians rarely complied with these requests.

Keerthi Gogineni, MD, of the Hospital of the University of Pennsylvania in Philadelphia, and colleagues  reported these findings in JAMA Oncology.

The researchers analyzed interviews with clinicians immediately after they visited with patients to assess whether a patient had made a request, the type of request made, and the clinical appropriateness of it.

The interviews were conducted at outpatient oncology facilities at 3 Philadelphia-area hospitals between October 2013 and June 2014.

The authors evaluated 5050 patient-clinician encounters involving 3624 patients and 60 clinicians. Most of the patients were women, and the most common cancer was hematologic.

Overall, 440 (8.7%) of the encounters included a patient demand or request, such as for imaging studies, treatments, or tests. And physicians complied with 365 (83%) of them.

Of all the patient-clinician encounters, 50 (1%) included a clinically inappropriate request. Clinicians complied with 7 of them. So, in 0.14% of encounters, clinicians ordered a test or treatment based on a clinically inappropriate request.

“At least in oncology, ‘demanding patients’ seem infrequent and may not account for a significant proportion of costs,” the researchers concluded.

In a related editorial, Anthony L. Back, MD, of the Seattle Cancer Care Alliance in Washington, wrote that inappropriate patient demands appear to be “more mythical than real.”

“[W]e have to stop blaming patients for being demanding,” he wrote. “In reality, it is hardly happening. The myth of the demanding patient is more about our own responses and how lackluster communication skills can contribute to difficult situations that stick in our throats and in our memories. And when we have calmed down enough to look up, we see that what is really happening between patients and physicians these days is something quite different.”

“It is possible that what the study by Gogineni et al documents is a point in the evolution of the patient-physician relationship when both sides recognize the complexity of cancer care belies a simple fix. Perhaps this ‘negative’ study is pointing to an important truth: that we need to redirect our attention from the myths that are distracting us.”

Doctor consults with a patient

Photo courtesy of NIH

Although it makes sense that patient requests might drive physicians to practice defensive medicine, new research suggests that may not be the case with cancer patients.

The study, conducted at outpatient oncology centers, showed that patients rarely made clinically inappropriate requests.

Only 1% of more than 5000 patient-clinician encounters resulted in a clinically inappropriate request. And physicians rarely complied with these requests.

Keerthi Gogineni, MD, of the Hospital of the University of Pennsylvania in Philadelphia, and colleagues  reported these findings in JAMA Oncology.

The researchers analyzed interviews with clinicians immediately after they visited with patients to assess whether a patient had made a request, the type of request made, and the clinical appropriateness of it.

The interviews were conducted at outpatient oncology facilities at 3 Philadelphia-area hospitals between October 2013 and June 2014.

The authors evaluated 5050 patient-clinician encounters involving 3624 patients and 60 clinicians. Most of the patients were women, and the most common cancer was hematologic.

Overall, 440 (8.7%) of the encounters included a patient demand or request, such as for imaging studies, treatments, or tests. And physicians complied with 365 (83%) of them.

Of all the patient-clinician encounters, 50 (1%) included a clinically inappropriate request. Clinicians complied with 7 of them. So, in 0.14% of encounters, clinicians ordered a test or treatment based on a clinically inappropriate request.

“At least in oncology, ‘demanding patients’ seem infrequent and may not account for a significant proportion of costs,” the researchers concluded.

In a related editorial, Anthony L. Back, MD, of the Seattle Cancer Care Alliance in Washington, wrote that inappropriate patient demands appear to be “more mythical than real.”

“[W]e have to stop blaming patients for being demanding,” he wrote. “In reality, it is hardly happening. The myth of the demanding patient is more about our own responses and how lackluster communication skills can contribute to difficult situations that stick in our throats and in our memories. And when we have calmed down enough to look up, we see that what is really happening between patients and physicians these days is something quite different.”

“It is possible that what the study by Gogineni et al documents is a point in the evolution of the patient-physician relationship when both sides recognize the complexity of cancer care belies a simple fix. Perhaps this ‘negative’ study is pointing to an important truth: that we need to redirect our attention from the myths that are distracting us.”

Doctor holding a clipboard

Researchers have identified 8 highly specific physical and cognitive signs that seem to be associated with imminent death in cancer patients.

The findings, published in Cancer, could offer clinicians the ability to better communicate with patients and their families.

The research might also help guide the medical team and caregivers when it comes to complex decision making, such as discontinuing tests and therapy, plans for hospital discharge, and hospice referral.

Previous studies in end-of-life care have focused on physicians prognosticating better. However, research on how to tell if a patient has entered the final days of life has been minimal, according to David Hui, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“In the past, studies trying to understand the signs associated with impending death were conducted in people who were recognized as dying, so there’s a potential bias built into this model,” Dr Hui said.

“With our study, we observed a list of signs in patients from the time they were admitted to the palliative care unit. They were observed systematically, twice a day, without knowing if the patient would die or be discharged.”

Dr Hui and his colleagues observed 357 cancer patients, 57% of whom ultimately died. The researchers observed 52 physical and cognitive signs—identified by Dr Hui and his colleagues in previous research—twice a day from the patient’s admission to discharge or death.

Of those 52 signs, the 8 most highly associated with impending death within 3 days were:

• Nonreactive pupils
• Decreased response to verbal stimuli
• Decreased response to visual stimuli
• Inability to close eyelids
• Drooping of the nasolabial fold
• Neck hyperextension
• Grunting of vocal cords
• Upper gastrointestinal bleeding.

“When cancer patients reach the last days of life, this is an extremely emotional time for families; their stress levels cannot be understated,” Dr Hui said.

“Knowing when death is imminent would provide more information so caregivers can plan appropriately. For clinicians, having this information could help reassure families that we are providing the best care possible.”

Dr Hui stressed that this research is not yet practice-changing, but is an important step in understanding these 8 signs and their relation to impending death. In addition, the findings are only representative of imminent cancer death and should not be generalized to other causes of death.

Follow-up studies in different settings are planned. Dr Hui and his colleagues plan to look at the reliability of the identified signs, as well as evaluate this research in other countries and in the hospice setting.

Doctor holding a clipboard

Researchers have identified 8 highly specific physical and cognitive signs that seem to be associated with imminent death in cancer patients.

The findings, published in Cancer, could offer clinicians the ability to better communicate with patients and their families.

The research might also help guide the medical team and caregivers when it comes to complex decision making, such as discontinuing tests and therapy, plans for hospital discharge, and hospice referral.

Previous studies in end-of-life care have focused on physicians prognosticating better. However, research on how to tell if a patient has entered the final days of life has been minimal, according to David Hui, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“In the past, studies trying to understand the signs associated with impending death were conducted in people who were recognized as dying, so there’s a potential bias built into this model,” Dr Hui said.

“With our study, we observed a list of signs in patients from the time they were admitted to the palliative care unit. They were observed systematically, twice a day, without knowing if the patient would die or be discharged.”

Dr Hui and his colleagues observed 357 cancer patients, 57% of whom ultimately died. The researchers observed 52 physical and cognitive signs—identified by Dr Hui and his colleagues in previous research—twice a day from the patient’s admission to discharge or death.

Of those 52 signs, the 8 most highly associated with impending death within 3 days were:

• Nonreactive pupils
• Decreased response to verbal stimuli
• Decreased response to visual stimuli
• Inability to close eyelids
• Drooping of the nasolabial fold
• Neck hyperextension
• Grunting of vocal cords
• Upper gastrointestinal bleeding.

“When cancer patients reach the last days of life, this is an extremely emotional time for families; their stress levels cannot be understated,” Dr Hui said.

“Knowing when death is imminent would provide more information so caregivers can plan appropriately. For clinicians, having this information could help reassure families that we are providing the best care possible.”

Dr Hui stressed that this research is not yet practice-changing, but is an important step in understanding these 8 signs and their relation to impending death. In addition, the findings are only representative of imminent cancer death and should not be generalized to other causes of death.

Follow-up studies in different settings are planned. Dr Hui and his colleagues plan to look at the reliability of the identified signs, as well as evaluate this research in other countries and in the hospice setting.

Doctor holding a clipboard

Researchers have identified 8 highly specific physical and cognitive signs that seem to be associated with imminent death in cancer patients.

The findings, published in Cancer, could offer clinicians the ability to better communicate with patients and their families.

The research might also help guide the medical team and caregivers when it comes to complex decision making, such as discontinuing tests and therapy, plans for hospital discharge, and hospice referral.

Previous studies in end-of-life care have focused on physicians prognosticating better. However, research on how to tell if a patient has entered the final days of life has been minimal, according to David Hui, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“In the past, studies trying to understand the signs associated with impending death were conducted in people who were recognized as dying, so there’s a potential bias built into this model,” Dr Hui said.

“With our study, we observed a list of signs in patients from the time they were admitted to the palliative care unit. They were observed systematically, twice a day, without knowing if the patient would die or be discharged.”

Dr Hui and his colleagues observed 357 cancer patients, 57% of whom ultimately died. The researchers observed 52 physical and cognitive signs—identified by Dr Hui and his colleagues in previous research—twice a day from the patient’s admission to discharge or death.

Of those 52 signs, the 8 most highly associated with impending death within 3 days were:

• Nonreactive pupils
• Decreased response to verbal stimuli
• Decreased response to visual stimuli
• Inability to close eyelids
• Drooping of the nasolabial fold
• Neck hyperextension
• Grunting of vocal cords
• Upper gastrointestinal bleeding.

“When cancer patients reach the last days of life, this is an extremely emotional time for families; their stress levels cannot be understated,” Dr Hui said.

“Knowing when death is imminent would provide more information so caregivers can plan appropriately. For clinicians, having this information could help reassure families that we are providing the best care possible.”

Dr Hui stressed that this research is not yet practice-changing, but is an important step in understanding these 8 signs and their relation to impending death. In addition, the findings are only representative of imminent cancer death and should not be generalized to other causes of death.

Follow-up studies in different settings are planned. Dr Hui and his colleagues plan to look at the reliability of the identified signs, as well as evaluate this research in other countries and in the hospice setting.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Prescription medications

Photo courtesy of CDC

New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).

The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.

“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.

“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”

Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.

The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.

In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.

The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.

The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.

“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”

The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.

“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.

Bertie Gottgens, PhD

Photo courtesy of

University of Cambridge

A new computer model that simulates blood cell development could aid the discovery of novel treatments for hematologic malignancies, according to researchers.

“With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory, dramatically speeding up research into blood development and the genetic mutations that cause leukemia,” said Bertie Gottgens, PhD, of the University of Cambridge in the UK.

Dr Gottgens and his colleagues explained this research in Nature Biotechnology.

To start, the researchers measured the activity of 48 genes in 3934 hematopoietic progenitor cells. They used the resulting dataset to construct the computer model of blood cell development, using computational approaches originally developed at Microsoft Research for the synthesis of computer code.

Subsequent lab experiments validated the accuracy of the model.

The researchers noted that the model can be used to simulate the activity of key genes implicated in hematologic malignancies. For example, around 1 in 5 children who develop leukemia have a faulty version of the RUNX1 gene, as do a similar proportion of adults with acute myeloid leukemia.

The computer model shows how RUNX1 interacts with other genes to control blood cell development. The gene produces the RUNX1 protein, which, in healthy patients, activates a network of key genes. In leukemia patients, an altered form of the protein is thought to suppress the network.

If the researchers change the “rules” in the network model, they can simulate the formation of abnormal leukemia cells. By tweaking the leukemia model until the behavior of the network reverts back to normal, the team can identify pathways that, potentially, could be targeted with drugs.

“Because the computer simulations are very fast, we can quickly screen through lots of possibilities to pick the most promising ones as pathways for drug development,” Dr Gottgens said.

“The cost of developing a new drug is enormous, and much of this cost comes from new candidate drugs failing late in the drug development process. Our model could significantly reduce the risk of failure, with the potential to make drug discovery faster and cheaper.”

Bertie Gottgens, PhD

Photo courtesy of

University of Cambridge

A new computer model that simulates blood cell development could aid the discovery of novel treatments for hematologic malignancies, according to researchers.

“With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory, dramatically speeding up research into blood development and the genetic mutations that cause leukemia,” said Bertie Gottgens, PhD, of the University of Cambridge in the UK.

Dr Gottgens and his colleagues explained this research in Nature Biotechnology.

To start, the researchers measured the activity of 48 genes in 3934 hematopoietic progenitor cells. They used the resulting dataset to construct the computer model of blood cell development, using computational approaches originally developed at Microsoft Research for the synthesis of computer code.

Subsequent lab experiments validated the accuracy of the model.

The researchers noted that the model can be used to simulate the activity of key genes implicated in hematologic malignancies. For example, around 1 in 5 children who develop leukemia have a faulty version of the RUNX1 gene, as do a similar proportion of adults with acute myeloid leukemia.

The computer model shows how RUNX1 interacts with other genes to control blood cell development. The gene produces the RUNX1 protein, which, in healthy patients, activates a network of key genes. In leukemia patients, an altered form of the protein is thought to suppress the network.

If the researchers change the “rules” in the network model, they can simulate the formation of abnormal leukemia cells. By tweaking the leukemia model until the behavior of the network reverts back to normal, the team can identify pathways that, potentially, could be targeted with drugs.

“Because the computer simulations are very fast, we can quickly screen through lots of possibilities to pick the most promising ones as pathways for drug development,” Dr Gottgens said.

“The cost of developing a new drug is enormous, and much of this cost comes from new candidate drugs failing late in the drug development process. Our model could significantly reduce the risk of failure, with the potential to make drug discovery faster and cheaper.”

Bertie Gottgens, PhD

Photo courtesy of

University of Cambridge

A new computer model that simulates blood cell development could aid the discovery of novel treatments for hematologic malignancies, according to researchers.

“With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory, dramatically speeding up research into blood development and the genetic mutations that cause leukemia,” said Bertie Gottgens, PhD, of the University of Cambridge in the UK.

Dr Gottgens and his colleagues explained this research in Nature Biotechnology.

To start, the researchers measured the activity of 48 genes in 3934 hematopoietic progenitor cells. They used the resulting dataset to construct the computer model of blood cell development, using computational approaches originally developed at Microsoft Research for the synthesis of computer code.

Subsequent lab experiments validated the accuracy of the model.

The researchers noted that the model can be used to simulate the activity of key genes implicated in hematologic malignancies. For example, around 1 in 5 children who develop leukemia have a faulty version of the RUNX1 gene, as do a similar proportion of adults with acute myeloid leukemia.

The computer model shows how RUNX1 interacts with other genes to control blood cell development. The gene produces the RUNX1 protein, which, in healthy patients, activates a network of key genes. In leukemia patients, an altered form of the protein is thought to suppress the network.

If the researchers change the “rules” in the network model, they can simulate the formation of abnormal leukemia cells. By tweaking the leukemia model until the behavior of the network reverts back to normal, the team can identify pathways that, potentially, could be targeted with drugs.

“Because the computer simulations are very fast, we can quickly screen through lots of possibilities to pick the most promising ones as pathways for drug development,” Dr Gottgens said.

“The cost of developing a new drug is enormous, and much of this cost comes from new candidate drugs failing late in the drug development process. Our model could significantly reduce the risk of failure, with the potential to make drug discovery faster and cheaper.”