Leukemia, Myelodysplasia, Transplantation

Cell culture in a petri dish

Results of a pilot study suggest safe transplantation of spermatogonial stem cells (SSCs) may be possible, potentially bringing us one step closer to ensuring fertility preservation in young boys with cancer.

Investigators found they could culture a large amount of SSCs using testicular tissue from boys with acute lymphoblastic leukemia (ALL).

And the ALL cells did not survive the culture process.

The researchers reported these results in Fertility and Sterility.

“Our study addressed an important safety issue—whether cancer cells that might be present in testicular tissue samples can survive the process to replicate the sperm-producing stem cells,” said study author Hooman Sadri-Ardekani, MD, PhD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

“This is an important consideration because of the potential to re-introduce cancer into the patient. The research, which involved one of the most common childhood cancers, shows that the cancer cells were eliminated. Based on these findings, we recommend that all boys with cancer be offered the option of storing testicular tissue for possible future clinical use.”

Previous research had shown that up to 30% of boys with ALL had cancer cells in their testicular tissue. In several studies, researchers attempted to eliminate cancer cells from biopsy tissue, but the results varied.

So Dr Sadri-Ardekani and his colleagues decided to investigate whether cancer cells would survive the protocol they had developed to reproduce SSCs from a small tissue biopsy.

This process multiplies the original SSCs by 18,000-fold so there are enough cells to transplant back into the patient when he reaches adulthood.

The investigators tested the method using samples from 3 ALL patients. The team cultured the ALL cells alone and at various concentrations in combination with testicular cells.

The ALL cells cultured alone did not survive beyond 14 days. But the testicular cells cultured in parallel survived and continue to proliferate well after 8 weeks.

At 10 to 16 days, the ALL cells cultured in combination had begun to die off. The cells were undetectable in cultures from 2 of the patients that had an initial ALL concentration of 0.04%, 0.4%, or 4%.

At 20 to 26 days, ALL cells were undetectable in all cultures, even those with an initial concentration of 40% ALL cells.

“This pilot study showed that the culture system not only allowed for efficient propagation of sperm stem cells but also eliminated ALL cells,” Dr Sadri-Ardekani said.

SSC transplants have not yet been attempted in humans, but they have been performed successfully in several species of animals, including monkeys.

Dr Sadri-Ardekani noted that before we can perform SSC transplants in patients, additional research is needed, particularly, research investigating whether other types of leukemia cells will also be eliminated in the cell-propagation process.

Cell culture in a petri dish

Results of a pilot study suggest safe transplantation of spermatogonial stem cells (SSCs) may be possible, potentially bringing us one step closer to ensuring fertility preservation in young boys with cancer.

Investigators found they could culture a large amount of SSCs using testicular tissue from boys with acute lymphoblastic leukemia (ALL).

And the ALL cells did not survive the culture process.

The researchers reported these results in Fertility and Sterility.

“Our study addressed an important safety issue—whether cancer cells that might be present in testicular tissue samples can survive the process to replicate the sperm-producing stem cells,” said study author Hooman Sadri-Ardekani, MD, PhD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

“This is an important consideration because of the potential to re-introduce cancer into the patient. The research, which involved one of the most common childhood cancers, shows that the cancer cells were eliminated. Based on these findings, we recommend that all boys with cancer be offered the option of storing testicular tissue for possible future clinical use.”

Previous research had shown that up to 30% of boys with ALL had cancer cells in their testicular tissue. In several studies, researchers attempted to eliminate cancer cells from biopsy tissue, but the results varied.

So Dr Sadri-Ardekani and his colleagues decided to investigate whether cancer cells would survive the protocol they had developed to reproduce SSCs from a small tissue biopsy.

This process multiplies the original SSCs by 18,000-fold so there are enough cells to transplant back into the patient when he reaches adulthood.

The investigators tested the method using samples from 3 ALL patients. The team cultured the ALL cells alone and at various concentrations in combination with testicular cells.

The ALL cells cultured alone did not survive beyond 14 days. But the testicular cells cultured in parallel survived and continue to proliferate well after 8 weeks.

At 10 to 16 days, the ALL cells cultured in combination had begun to die off. The cells were undetectable in cultures from 2 of the patients that had an initial ALL concentration of 0.04%, 0.4%, or 4%.

At 20 to 26 days, ALL cells were undetectable in all cultures, even those with an initial concentration of 40% ALL cells.

“This pilot study showed that the culture system not only allowed for efficient propagation of sperm stem cells but also eliminated ALL cells,” Dr Sadri-Ardekani said.

SSC transplants have not yet been attempted in humans, but they have been performed successfully in several species of animals, including monkeys.

Dr Sadri-Ardekani noted that before we can perform SSC transplants in patients, additional research is needed, particularly, research investigating whether other types of leukemia cells will also be eliminated in the cell-propagation process.

Cell culture in a petri dish

Results of a pilot study suggest safe transplantation of spermatogonial stem cells (SSCs) may be possible, potentially bringing us one step closer to ensuring fertility preservation in young boys with cancer.

Investigators found they could culture a large amount of SSCs using testicular tissue from boys with acute lymphoblastic leukemia (ALL).

And the ALL cells did not survive the culture process.

The researchers reported these results in Fertility and Sterility.

“Our study addressed an important safety issue—whether cancer cells that might be present in testicular tissue samples can survive the process to replicate the sperm-producing stem cells,” said study author Hooman Sadri-Ardekani, MD, PhD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina.

“This is an important consideration because of the potential to re-introduce cancer into the patient. The research, which involved one of the most common childhood cancers, shows that the cancer cells were eliminated. Based on these findings, we recommend that all boys with cancer be offered the option of storing testicular tissue for possible future clinical use.”

Previous research had shown that up to 30% of boys with ALL had cancer cells in their testicular tissue. In several studies, researchers attempted to eliminate cancer cells from biopsy tissue, but the results varied.

So Dr Sadri-Ardekani and his colleagues decided to investigate whether cancer cells would survive the protocol they had developed to reproduce SSCs from a small tissue biopsy.

This process multiplies the original SSCs by 18,000-fold so there are enough cells to transplant back into the patient when he reaches adulthood.

The investigators tested the method using samples from 3 ALL patients. The team cultured the ALL cells alone and at various concentrations in combination with testicular cells.

The ALL cells cultured alone did not survive beyond 14 days. But the testicular cells cultured in parallel survived and continue to proliferate well after 8 weeks.

At 10 to 16 days, the ALL cells cultured in combination had begun to die off. The cells were undetectable in cultures from 2 of the patients that had an initial ALL concentration of 0.04%, 0.4%, or 4%.

At 20 to 26 days, ALL cells were undetectable in all cultures, even those with an initial concentration of 40% ALL cells.

“This pilot study showed that the culture system not only allowed for efficient propagation of sperm stem cells but also eliminated ALL cells,” Dr Sadri-Ardekani said.

SSC transplants have not yet been attempted in humans, but they have been performed successfully in several species of animals, including monkeys.

Dr Sadri-Ardekani noted that before we can perform SSC transplants in patients, additional research is needed, particularly, research investigating whether other types of leukemia cells will also be eliminated in the cell-propagation process.

Nurse treating cancer patient

Credit: Rhoda Baer

A new report shows the rate of invasive cancer among US men and women dropped slightly from 2009 to 2010, and the most common cancers were solid tumor malignancies.

However, non-Hodgkin lymphoma (NHL) consistently rated among the top 10 most common cancers, regardless of patient gender or race.

The report was prepared by the Centers for Disease Control and Prevention (CDC) and appears in the current Morbidity and Mortality Weekly Report.

Researchers analyzed new cases of invasive cancers diagnosed in 2010 and reported to the CDC’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology and Results Program.

Data from all states (except Arkansas and Minnesota) and the District of Columbia were included in the analysis, which covered 97% of the US population.

The researchers found the rates of invasive cancer cases dropped from 459 per 100,000 people in 2009 to 446 per 100,000 in 2010.

Cancer rates were higher among men (503 per 100,000) than women (405 per 100,000). In all, there were 745,383 cases reported among men and 711,113 among women in 2010.

The highest rates were for cancers of the prostate (126 per 100,000), female breast (119 per 100,000), lung and bronchus (62 per 100,000), and colon and rectum (40 per 100,000). Together, these accounted for half of all cancer cases in the US.

However, hematologic malignancies were fairly common as well. NHL was the 6th most common cancer for men of all races/ethnicities except Hispanic. For this group, NHL was the 4th most common cancer.

NHL was the 7th most common cancer for black and white women and 6th for the remaining groups, which included American Indian/Alaskan native, Asian/Pacific Islander, and Hispanic women.

Leukemia and myeloma were also among the top 10 most common invasive cancers for certain patients.

Leukemia was the 9th most common cancer for Hispanic and white men and the 10th for American Indian/Alaskan Native women. Myeloma was the 8th most common cancer for black women.

Overall, cancer rates were highest among black patients (455 per 100,000), followed by whites (445 per 100,000), Hispanics (344 per 100,000), Asian/Pacific Islanders (289 per 100,000), and American Indians/Alaskan Natives (270 per 100,000).

Nurse treating cancer patient

Credit: Rhoda Baer

A new report shows the rate of invasive cancer among US men and women dropped slightly from 2009 to 2010, and the most common cancers were solid tumor malignancies.

However, non-Hodgkin lymphoma (NHL) consistently rated among the top 10 most common cancers, regardless of patient gender or race.

The report was prepared by the Centers for Disease Control and Prevention (CDC) and appears in the current Morbidity and Mortality Weekly Report.

Researchers analyzed new cases of invasive cancers diagnosed in 2010 and reported to the CDC’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology and Results Program.

Data from all states (except Arkansas and Minnesota) and the District of Columbia were included in the analysis, which covered 97% of the US population.

The researchers found the rates of invasive cancer cases dropped from 459 per 100,000 people in 2009 to 446 per 100,000 in 2010.

Cancer rates were higher among men (503 per 100,000) than women (405 per 100,000). In all, there were 745,383 cases reported among men and 711,113 among women in 2010.

The highest rates were for cancers of the prostate (126 per 100,000), female breast (119 per 100,000), lung and bronchus (62 per 100,000), and colon and rectum (40 per 100,000). Together, these accounted for half of all cancer cases in the US.

However, hematologic malignancies were fairly common as well. NHL was the 6th most common cancer for men of all races/ethnicities except Hispanic. For this group, NHL was the 4th most common cancer.

NHL was the 7th most common cancer for black and white women and 6th for the remaining groups, which included American Indian/Alaskan native, Asian/Pacific Islander, and Hispanic women.

Leukemia and myeloma were also among the top 10 most common invasive cancers for certain patients.

Leukemia was the 9th most common cancer for Hispanic and white men and the 10th for American Indian/Alaskan Native women. Myeloma was the 8th most common cancer for black women.

Overall, cancer rates were highest among black patients (455 per 100,000), followed by whites (445 per 100,000), Hispanics (344 per 100,000), Asian/Pacific Islanders (289 per 100,000), and American Indians/Alaskan Natives (270 per 100,000).

Nurse treating cancer patient

Credit: Rhoda Baer

A new report shows the rate of invasive cancer among US men and women dropped slightly from 2009 to 2010, and the most common cancers were solid tumor malignancies.

However, non-Hodgkin lymphoma (NHL) consistently rated among the top 10 most common cancers, regardless of patient gender or race.

The report was prepared by the Centers for Disease Control and Prevention (CDC) and appears in the current Morbidity and Mortality Weekly Report.

Researchers analyzed new cases of invasive cancers diagnosed in 2010 and reported to the CDC’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology and Results Program.

Data from all states (except Arkansas and Minnesota) and the District of Columbia were included in the analysis, which covered 97% of the US population.

The researchers found the rates of invasive cancer cases dropped from 459 per 100,000 people in 2009 to 446 per 100,000 in 2010.

Cancer rates were higher among men (503 per 100,000) than women (405 per 100,000). In all, there were 745,383 cases reported among men and 711,113 among women in 2010.

The highest rates were for cancers of the prostate (126 per 100,000), female breast (119 per 100,000), lung and bronchus (62 per 100,000), and colon and rectum (40 per 100,000). Together, these accounted for half of all cancer cases in the US.

However, hematologic malignancies were fairly common as well. NHL was the 6th most common cancer for men of all races/ethnicities except Hispanic. For this group, NHL was the 4th most common cancer.

NHL was the 7th most common cancer for black and white women and 6th for the remaining groups, which included American Indian/Alaskan native, Asian/Pacific Islander, and Hispanic women.

Leukemia and myeloma were also among the top 10 most common invasive cancers for certain patients.

Leukemia was the 9th most common cancer for Hispanic and white men and the 10th for American Indian/Alaskan Native women. Myeloma was the 8th most common cancer for black women.

Overall, cancer rates were highest among black patients (455 per 100,000), followed by whites (445 per 100,000), Hispanics (344 per 100,000), Asian/Pacific Islanders (289 per 100,000), and American Indians/Alaskan Natives (270 per 100,000).

Hairy cell leukemia (HCL) is a B-cell chronic lymphoproliferative disorder that was initially described as leukemic reticuloendotheliosis. The disease is characterized by monocytopenia, organomegaly, constitutional symptoms, and bone marrow fibrosis. Significant advances have improved the diagnosis and management of HCL over the last 55 years. Although HCL has an indolent course, most patients will require treatment of the disease. Indications to initiate therapy include disease-related symptoms, signs of bone marrow failure, or frequent infections. Asymptomatic patients without cytopenias can be observed without the need for therapeutic interventions. Therapeutic options usually consist of chemotherapy, immunotherapy, biological agents, and surgery.

Click on the PDF icon at the top of this introduction to read the full article.

Hairy cell leukemia (HCL) is a B-cell chronic lymphoproliferative disorder that was initially described as leukemic reticuloendotheliosis. The disease is characterized by monocytopenia, organomegaly, constitutional symptoms, and bone marrow fibrosis. Significant advances have improved the diagnosis and management of HCL over the last 55 years. Although HCL has an indolent course, most patients will require treatment of the disease. Indications to initiate therapy include disease-related symptoms, signs of bone marrow failure, or frequent infections. Asymptomatic patients without cytopenias can be observed without the need for therapeutic interventions. Therapeutic options usually consist of chemotherapy, immunotherapy, biological agents, and surgery.

Click on the PDF icon at the top of this introduction to read the full article.

Hairy cell leukemia (HCL) is a B-cell chronic lymphoproliferative disorder that was initially described as leukemic reticuloendotheliosis. The disease is characterized by monocytopenia, organomegaly, constitutional symptoms, and bone marrow fibrosis. Significant advances have improved the diagnosis and management of HCL over the last 55 years. Although HCL has an indolent course, most patients will require treatment of the disease. Indications to initiate therapy include disease-related symptoms, signs of bone marrow failure, or frequent infections. Asymptomatic patients without cytopenias can be observed without the need for therapeutic interventions. Therapeutic options usually consist of chemotherapy, immunotherapy, biological agents, and surgery.

Click on the PDF icon at the top of this introduction to read the full article.

NK cell destroying a cancer cell

Credit: St Jude Children’s

Research Hospital

Researchers say they’ve gained new insight into the production of natural killer (NK) cells.

And their findings may help them generate greater numbers of the cells in culture, which could have implications for the treatment of leukemia and other malignancies.

A previous study conducted by the same team revealed that the gene E4bp4 must be switched on to allow the immune system to produce NK cells.

Their new work suggests that E4bp4 expression is required for progenitor cells to commit to the NK lineage. And the gene promotes NK-cell development by regulating expression of the transcription factors Eomes and Id2.

The researchers described these discoveries in the Journal of Experimental Medicine.

“We are excited to find that E4bp4 has such a crucial role in determining the decisive point where blood progenitor cells become NK cells,” said study author Hugh Brady, of Imperial College London in the UK.

“We are now starting to apply this to human blood stem cells to work out how switching on E4bp4 can allow us to make lots of robust human NK cells in culture. We are hoping to make human NK cells that will have improved survival and be very toxic to cancer cells when transfused into patients. Hopefully, this will allow a big reduction in the number of NK cells needed to treat an individual patient.”

To gain insight into NK-cell production, Dr Brady and his colleagues evaluated 2 types of mice with NK-cell deficiencies. The Il15ra knockout mouse model cannot mediate IL-15 signaling, which is critical for NK-cell production. And the T-bet (Tbx21) knockout model lacks a transcription factor that’s crucial for NK-cell development.

Analysis of the Il15ra model revealed that the absence of E4bp4 perturbs NK-cell development earlier than the absence of IL-15 signaling. This suggests E4bp4 acts before IL-15, which was previously considered the definitive factor required for NK-cell production.

The researchers also found that E4bp4 is required for the production of NK progenitors, but T-bet is not. And this suggests E4bp4 acts before T-bet in NK-cell development.

To investigate these findings further, the team took cells at various stages of NK-cell differentiation from wild-type bone marrow and measured their expression of transcription factor mRNAs.

They detected E4bp4 transcript in both lymphoid-primed multipotent progenitors (LMPPs) and common lymphoid progenitors (CLPs), and E4bp4 expression increased at later stages of NK-cell development.

Based on these results, the researchers speculated that E4bp4 might be a lineage commitment factor controlling the development of NK progenitors from CLPs. To test that theory, they restored E4bp4 expression in purified E4bp4-/- CLPs to see if this could re-establish NK-cell development.

The team sorted CLPs from E4bp4-/- bone marrow, cultured them in lymphocyte-inducing conditions, transduced them with E4bp4 or empty vector, and moved on to NK-cell-inducing conditions. But neither cell type produced NK cells.

So the researchers decided to initiate the culture at an earlier developmental stage, using LMPPs. They cultured LMPPs, which exhibited a CLP phenotype at the time of transduction. And CLPs transduced with E4bp4 gave rise to NK cells, but CLPs transduced with empty vector did not.

As these results suggest that E4bp4 acts at the earliest possible point in NK-cell development, the team wanted to characterize E4bp4’s relationship with transcription factors that are likely to act downstream.

They tested several transcription factors known to play a part in NK-cell production and function. But only Eomes and Id2 proved essential for E4bp4 to direct the production of fully functional, mature NK cells.

NK cell destroying a cancer cell

Credit: St Jude Children’s

Research Hospital

Researchers say they’ve gained new insight into the production of natural killer (NK) cells.

And their findings may help them generate greater numbers of the cells in culture, which could have implications for the treatment of leukemia and other malignancies.

A previous study conducted by the same team revealed that the gene E4bp4 must be switched on to allow the immune system to produce NK cells.

Their new work suggests that E4bp4 expression is required for progenitor cells to commit to the NK lineage. And the gene promotes NK-cell development by regulating expression of the transcription factors Eomes and Id2.

The researchers described these discoveries in the Journal of Experimental Medicine.

“We are excited to find that E4bp4 has such a crucial role in determining the decisive point where blood progenitor cells become NK cells,” said study author Hugh Brady, of Imperial College London in the UK.

“We are now starting to apply this to human blood stem cells to work out how switching on E4bp4 can allow us to make lots of robust human NK cells in culture. We are hoping to make human NK cells that will have improved survival and be very toxic to cancer cells when transfused into patients. Hopefully, this will allow a big reduction in the number of NK cells needed to treat an individual patient.”

To gain insight into NK-cell production, Dr Brady and his colleagues evaluated 2 types of mice with NK-cell deficiencies. The Il15ra knockout mouse model cannot mediate IL-15 signaling, which is critical for NK-cell production. And the T-bet (Tbx21) knockout model lacks a transcription factor that’s crucial for NK-cell development.

Analysis of the Il15ra model revealed that the absence of E4bp4 perturbs NK-cell development earlier than the absence of IL-15 signaling. This suggests E4bp4 acts before IL-15, which was previously considered the definitive factor required for NK-cell production.

The researchers also found that E4bp4 is required for the production of NK progenitors, but T-bet is not. And this suggests E4bp4 acts before T-bet in NK-cell development.

To investigate these findings further, the team took cells at various stages of NK-cell differentiation from wild-type bone marrow and measured their expression of transcription factor mRNAs.

They detected E4bp4 transcript in both lymphoid-primed multipotent progenitors (LMPPs) and common lymphoid progenitors (CLPs), and E4bp4 expression increased at later stages of NK-cell development.

Based on these results, the researchers speculated that E4bp4 might be a lineage commitment factor controlling the development of NK progenitors from CLPs. To test that theory, they restored E4bp4 expression in purified E4bp4-/- CLPs to see if this could re-establish NK-cell development.

The team sorted CLPs from E4bp4-/- bone marrow, cultured them in lymphocyte-inducing conditions, transduced them with E4bp4 or empty vector, and moved on to NK-cell-inducing conditions. But neither cell type produced NK cells.

So the researchers decided to initiate the culture at an earlier developmental stage, using LMPPs. They cultured LMPPs, which exhibited a CLP phenotype at the time of transduction. And CLPs transduced with E4bp4 gave rise to NK cells, but CLPs transduced with empty vector did not.

As these results suggest that E4bp4 acts at the earliest possible point in NK-cell development, the team wanted to characterize E4bp4’s relationship with transcription factors that are likely to act downstream.

They tested several transcription factors known to play a part in NK-cell production and function. But only Eomes and Id2 proved essential for E4bp4 to direct the production of fully functional, mature NK cells.

NK cell destroying a cancer cell

Credit: St Jude Children’s

Research Hospital

Researchers say they’ve gained new insight into the production of natural killer (NK) cells.

And their findings may help them generate greater numbers of the cells in culture, which could have implications for the treatment of leukemia and other malignancies.

A previous study conducted by the same team revealed that the gene E4bp4 must be switched on to allow the immune system to produce NK cells.

Their new work suggests that E4bp4 expression is required for progenitor cells to commit to the NK lineage. And the gene promotes NK-cell development by regulating expression of the transcription factors Eomes and Id2.

The researchers described these discoveries in the Journal of Experimental Medicine.

“We are excited to find that E4bp4 has such a crucial role in determining the decisive point where blood progenitor cells become NK cells,” said study author Hugh Brady, of Imperial College London in the UK.

“We are now starting to apply this to human blood stem cells to work out how switching on E4bp4 can allow us to make lots of robust human NK cells in culture. We are hoping to make human NK cells that will have improved survival and be very toxic to cancer cells when transfused into patients. Hopefully, this will allow a big reduction in the number of NK cells needed to treat an individual patient.”

To gain insight into NK-cell production, Dr Brady and his colleagues evaluated 2 types of mice with NK-cell deficiencies. The Il15ra knockout mouse model cannot mediate IL-15 signaling, which is critical for NK-cell production. And the T-bet (Tbx21) knockout model lacks a transcription factor that’s crucial for NK-cell development.

Analysis of the Il15ra model revealed that the absence of E4bp4 perturbs NK-cell development earlier than the absence of IL-15 signaling. This suggests E4bp4 acts before IL-15, which was previously considered the definitive factor required for NK-cell production.

The researchers also found that E4bp4 is required for the production of NK progenitors, but T-bet is not. And this suggests E4bp4 acts before T-bet in NK-cell development.

To investigate these findings further, the team took cells at various stages of NK-cell differentiation from wild-type bone marrow and measured their expression of transcription factor mRNAs.

They detected E4bp4 transcript in both lymphoid-primed multipotent progenitors (LMPPs) and common lymphoid progenitors (CLPs), and E4bp4 expression increased at later stages of NK-cell development.

Based on these results, the researchers speculated that E4bp4 might be a lineage commitment factor controlling the development of NK progenitors from CLPs. To test that theory, they restored E4bp4 expression in purified E4bp4-/- CLPs to see if this could re-establish NK-cell development.

The team sorted CLPs from E4bp4-/- bone marrow, cultured them in lymphocyte-inducing conditions, transduced them with E4bp4 or empty vector, and moved on to NK-cell-inducing conditions. But neither cell type produced NK cells.

So the researchers decided to initiate the culture at an earlier developmental stage, using LMPPs. They cultured LMPPs, which exhibited a CLP phenotype at the time of transduction. And CLPs transduced with E4bp4 gave rise to NK cells, but CLPs transduced with empty vector did not.

As these results suggest that E4bp4 acts at the earliest possible point in NK-cell development, the team wanted to characterize E4bp4’s relationship with transcription factors that are likely to act downstream.

They tested several transcription factors known to play a part in NK-cell production and function. But only Eomes and Id2 proved essential for E4bp4 to direct the production of fully functional, mature NK cells.

Chromosomes

Credit: Beth A. Sullivan

Individuals with a rare chromosomal abnormality have a 2700-fold increased risk of developing a type of acute lymphoblastic leukemia (ALL), according to a study published in Nature.

Previous research showed that a small subset of ALL patients have recurrent amplification of megabase regions of chromosome 21.

In the current study, investigators decided to reconstruct the sequence of genetic events that lead to this type of leukemia, iAMP21 ALL.

They found that some patients with iAMP21 ALL had an abnormality in which chromosome 15 and chromosome 21 are fused together, known as a Robertsonian translocation.

And the joining of these 2 chromosomes increased a person’s risk of developing iAMP21 ALL 2700-fold, when compared to the general population.

“Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL,” said study author Christine Harrison, PhD, of Newcastle University in the UK.

“We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome.”

To do this, the investigators sequenced 9 samples from patients with iAMP21 ALL, 4 with the rare Robertsonian translocation and 5 without it.

For the 4 patients with the translocation, their leukemia was initiated by chromothripsis. This event shatters a chromosome—in this case, the joined chromosomes 15 and 21—and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order.

In the 5 other patients, the cancer was initiated by 2 copies of chromosome 21 being fused together, head-to-head, usually followed by chromothripsis.

The investigators found a consistent sequence of genetic events across the patients studied. Although the events seem random and chaotic at first, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimized to drive leukemia.

“What is striking about our findings is that this type of leukemia could develop incredibly quickly—potentially in just a few rounds of cell division,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”

Chromosomes

Credit: Beth A. Sullivan

Individuals with a rare chromosomal abnormality have a 2700-fold increased risk of developing a type of acute lymphoblastic leukemia (ALL), according to a study published in Nature.

Previous research showed that a small subset of ALL patients have recurrent amplification of megabase regions of chromosome 21.

In the current study, investigators decided to reconstruct the sequence of genetic events that lead to this type of leukemia, iAMP21 ALL.

They found that some patients with iAMP21 ALL had an abnormality in which chromosome 15 and chromosome 21 are fused together, known as a Robertsonian translocation.

And the joining of these 2 chromosomes increased a person’s risk of developing iAMP21 ALL 2700-fold, when compared to the general population.

“Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL,” said study author Christine Harrison, PhD, of Newcastle University in the UK.

“We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome.”

To do this, the investigators sequenced 9 samples from patients with iAMP21 ALL, 4 with the rare Robertsonian translocation and 5 without it.

For the 4 patients with the translocation, their leukemia was initiated by chromothripsis. This event shatters a chromosome—in this case, the joined chromosomes 15 and 21—and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order.

In the 5 other patients, the cancer was initiated by 2 copies of chromosome 21 being fused together, head-to-head, usually followed by chromothripsis.

The investigators found a consistent sequence of genetic events across the patients studied. Although the events seem random and chaotic at first, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimized to drive leukemia.

“What is striking about our findings is that this type of leukemia could develop incredibly quickly—potentially in just a few rounds of cell division,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”

Chromosomes

Credit: Beth A. Sullivan

Individuals with a rare chromosomal abnormality have a 2700-fold increased risk of developing a type of acute lymphoblastic leukemia (ALL), according to a study published in Nature.

Previous research showed that a small subset of ALL patients have recurrent amplification of megabase regions of chromosome 21.

In the current study, investigators decided to reconstruct the sequence of genetic events that lead to this type of leukemia, iAMP21 ALL.

They found that some patients with iAMP21 ALL had an abnormality in which chromosome 15 and chromosome 21 are fused together, known as a Robertsonian translocation.

And the joining of these 2 chromosomes increased a person’s risk of developing iAMP21 ALL 2700-fold, when compared to the general population.

“Although rare, people who carry this specific joining together of chromosomes 15 and 21 are specifically and massively predisposed to iAMP21 ALL,” said study author Christine Harrison, PhD, of Newcastle University in the UK.

“We have been able to map the roads the cells follow in their transition from a normal genome to a leukemia genome.”

To do this, the investigators sequenced 9 samples from patients with iAMP21 ALL, 4 with the rare Robertsonian translocation and 5 without it.

For the 4 patients with the translocation, their leukemia was initiated by chromothripsis. This event shatters a chromosome—in this case, the joined chromosomes 15 and 21—and then the DNA repair machinery pastes the chromosome back together in a highly flawed and inaccurate order.

In the 5 other patients, the cancer was initiated by 2 copies of chromosome 21 being fused together, head-to-head, usually followed by chromothripsis.

The investigators found a consistent sequence of genetic events across the patients studied. Although the events seem random and chaotic at first, the end result is a new chromosome 21 in which the numbers and arrangement of genes are optimized to drive leukemia.

“What is striking about our findings is that this type of leukemia could develop incredibly quickly—potentially in just a few rounds of cell division,” said study author Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering.”

Cell culture in a petri dish

Two small-molecule compounds can help researchers maintain leukemic stem cells (LSCs) in culture, according to a paper published in Nature Methods.

Investigators said they created improved culture conditions for primary human acute myeloid leukemia (AML) cells, based on serum-free medium supplemented with the small molecules SR1 and UM729.

These conditions increased the yield of phenotypically undifferentiated CD34⁺ AML cells and supported the ex vivo maintenance of LSCs that are typically lost in culture.

Caroline Pabst, MD, of the Institute for Research in Immunology and Cancer at the University of Montreal in Quebec, Canada, and her colleagues conducted this research using AML patient samples.

The team screened about 6000 compounds in an attempt to identify small molecules that promote the ex vivo expansion of undifferentiated AML cells.

And they found that suppressors of the aryl-hydrocarbon receptor (AhR) pathway were enriched among the hit compounds.

So the researchers decided to study 2 chemically distinct AhR suppressors: N-methyl-β-carboline-3-carboxamide (C05), which yielded the highest CD34⁺CD15^- cell counts in secondary screens, and the known AhR antagonist SR1. They also studied the pyrimidoindole UM729, which had shown no effects on AhR target genes.

Experiments showed that the AhR pathway was “rapidly and robustly” activated in the AML samples upon culture. However, suppressing the pathway with SR1 and C05 enabled the expansion of CD34⁺ AML cells and supported the maintenance of LSCs.

In addition, UM729 had an additive effect with SR1 on the maintenance of AML stem and progenitor cells in vitro.

The investigators said these results should help establish defined conditions to overcome spontaneous differentiation and cell death in ex vivo cultures of primary human AML specimens.

The team believes at least 3 molecular targets could be involved in this process, and 2 of them are targeted by SR1 and UM729.

So these compounds could serve as a standardized supplement to culture media. They might aid studies of self-renewal mechanisms and help researchers identify new antileukemic drugs.

Cell culture in a petri dish

Two small-molecule compounds can help researchers maintain leukemic stem cells (LSCs) in culture, according to a paper published in Nature Methods.

Investigators said they created improved culture conditions for primary human acute myeloid leukemia (AML) cells, based on serum-free medium supplemented with the small molecules SR1 and UM729.

These conditions increased the yield of phenotypically undifferentiated CD34⁺ AML cells and supported the ex vivo maintenance of LSCs that are typically lost in culture.

Caroline Pabst, MD, of the Institute for Research in Immunology and Cancer at the University of Montreal in Quebec, Canada, and her colleagues conducted this research using AML patient samples.

The team screened about 6000 compounds in an attempt to identify small molecules that promote the ex vivo expansion of undifferentiated AML cells.

And they found that suppressors of the aryl-hydrocarbon receptor (AhR) pathway were enriched among the hit compounds.

So the researchers decided to study 2 chemically distinct AhR suppressors: N-methyl-β-carboline-3-carboxamide (C05), which yielded the highest CD34⁺CD15^- cell counts in secondary screens, and the known AhR antagonist SR1. They also studied the pyrimidoindole UM729, which had shown no effects on AhR target genes.

Experiments showed that the AhR pathway was “rapidly and robustly” activated in the AML samples upon culture. However, suppressing the pathway with SR1 and C05 enabled the expansion of CD34⁺ AML cells and supported the maintenance of LSCs.

In addition, UM729 had an additive effect with SR1 on the maintenance of AML stem and progenitor cells in vitro.

The investigators said these results should help establish defined conditions to overcome spontaneous differentiation and cell death in ex vivo cultures of primary human AML specimens.

The team believes at least 3 molecular targets could be involved in this process, and 2 of them are targeted by SR1 and UM729.

So these compounds could serve as a standardized supplement to culture media. They might aid studies of self-renewal mechanisms and help researchers identify new antileukemic drugs.

Cell culture in a petri dish

Two small-molecule compounds can help researchers maintain leukemic stem cells (LSCs) in culture, according to a paper published in Nature Methods.

Investigators said they created improved culture conditions for primary human acute myeloid leukemia (AML) cells, based on serum-free medium supplemented with the small molecules SR1 and UM729.

These conditions increased the yield of phenotypically undifferentiated CD34⁺ AML cells and supported the ex vivo maintenance of LSCs that are typically lost in culture.

Caroline Pabst, MD, of the Institute for Research in Immunology and Cancer at the University of Montreal in Quebec, Canada, and her colleagues conducted this research using AML patient samples.

The team screened about 6000 compounds in an attempt to identify small molecules that promote the ex vivo expansion of undifferentiated AML cells.

And they found that suppressors of the aryl-hydrocarbon receptor (AhR) pathway were enriched among the hit compounds.

So the researchers decided to study 2 chemically distinct AhR suppressors: N-methyl-β-carboline-3-carboxamide (C05), which yielded the highest CD34⁺CD15^- cell counts in secondary screens, and the known AhR antagonist SR1. They also studied the pyrimidoindole UM729, which had shown no effects on AhR target genes.

Experiments showed that the AhR pathway was “rapidly and robustly” activated in the AML samples upon culture. However, suppressing the pathway with SR1 and C05 enabled the expansion of CD34⁺ AML cells and supported the maintenance of LSCs.

In addition, UM729 had an additive effect with SR1 on the maintenance of AML stem and progenitor cells in vitro.

The investigators said these results should help establish defined conditions to overcome spontaneous differentiation and cell death in ex vivo cultures of primary human AML specimens.

The team believes at least 3 molecular targets could be involved in this process, and 2 of them are targeted by SR1 and UM729.

So these compounds could serve as a standardized supplement to culture media. They might aid studies of self-renewal mechanisms and help researchers identify new antileukemic drugs.

Doctor consulting with a

cancer patient and her father

Credit: Rhoda Baer

The “health gap” between childhood cancer survivors and their siblings widens with age, according to a study published in the Journal of Clinical Oncology.

Cancer survivors aged 20 to 34 years old were 3.8 times more likely than siblings of the same age to develop new cancers and other serious health conditions.

By age 35 and beyond, survivors had a 5-fold greater risk.

“Survivors remain at risk for serious health problems into their 40s and 50s, decades after they have completed treatment for childhood cancer,” said study author Gregory Armstrong, MD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.

“In fact, for survivors, the risk of illness and death increases significantly beyond the age of 35. Their siblings don’t share these same risks.”

Dr Armstrong and his colleagues uncovered these results by analyzing data from the Childhood Cancer Survivor Study, which included 14,359 survivors and 4301 healthy siblings.

The patients had been diagnosed with leukemias, lymphomas, and other pediatric cancers before age 21 and were followed for a median of 24.5 years (range, 5 to 39.3 years).

The researchers compared survivors to age-matched siblings, evaluating the incidence of severe, disabling, life-threatening, or fatal health conditions. This included new malignancies as well as diseases of the heart, lungs, liver, kidneys, and hormones.

The team found a heightened risk of these health conditions among cancer survivors. And that risk increased as the survivors aged.

At 20 years of age, 16% of survivors had serious health conditions, compared to 3.3% of siblings. But by age 50, the incidence had increased to 53.6% among survivors and 19.8% among siblings. At 50, 22.5% of survivors had at least 2 serious health problems, and 10.1% had 3 or more.

In a multivariate analysis, the hazard ratio for developing serious health conditions was significantly higher among survivors aged 35 and older than for those aged 20 to 34 (P=0.03).

Among survivors who reached age 35 without serious health problems, 25.9% developed a significant health problem in the next decade. In comparison, 6% of siblings developed their first serious health condition between the ages of 35 and 45.

In addition to showing a health gap between childhood cancer survivors and their siblings, this research adds to evidence that survivors experience accelerated aging. The 24-year-old cancer survivors had roughly the same cumulative incidence of grade 3 to 5 health conditions (19.6%) as the 50-year-old siblings (19.8%).

Overall, these findings highlight the importance of lifelong, risk-based healthcare for childhood cancer survivors, Dr Armstrong said. Depending on their cancer treatment and other risk factors, follow-up care may include performing health checks at a younger age than is recommended for the general public.

This study involved survivors whose cancer was diagnosed between 1970 and 1986. The researchers are now studying the health of adult cancer survivors from a more recent treatment era.

Doctor consulting with a

cancer patient and her father

Credit: Rhoda Baer

The “health gap” between childhood cancer survivors and their siblings widens with age, according to a study published in the Journal of Clinical Oncology.

Cancer survivors aged 20 to 34 years old were 3.8 times more likely than siblings of the same age to develop new cancers and other serious health conditions.

By age 35 and beyond, survivors had a 5-fold greater risk.

“Survivors remain at risk for serious health problems into their 40s and 50s, decades after they have completed treatment for childhood cancer,” said study author Gregory Armstrong, MD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.

“In fact, for survivors, the risk of illness and death increases significantly beyond the age of 35. Their siblings don’t share these same risks.”

Dr Armstrong and his colleagues uncovered these results by analyzing data from the Childhood Cancer Survivor Study, which included 14,359 survivors and 4301 healthy siblings.

The patients had been diagnosed with leukemias, lymphomas, and other pediatric cancers before age 21 and were followed for a median of 24.5 years (range, 5 to 39.3 years).

The researchers compared survivors to age-matched siblings, evaluating the incidence of severe, disabling, life-threatening, or fatal health conditions. This included new malignancies as well as diseases of the heart, lungs, liver, kidneys, and hormones.

The team found a heightened risk of these health conditions among cancer survivors. And that risk increased as the survivors aged.

At 20 years of age, 16% of survivors had serious health conditions, compared to 3.3% of siblings. But by age 50, the incidence had increased to 53.6% among survivors and 19.8% among siblings. At 50, 22.5% of survivors had at least 2 serious health problems, and 10.1% had 3 or more.

In a multivariate analysis, the hazard ratio for developing serious health conditions was significantly higher among survivors aged 35 and older than for those aged 20 to 34 (P=0.03).

Among survivors who reached age 35 without serious health problems, 25.9% developed a significant health problem in the next decade. In comparison, 6% of siblings developed their first serious health condition between the ages of 35 and 45.

In addition to showing a health gap between childhood cancer survivors and their siblings, this research adds to evidence that survivors experience accelerated aging. The 24-year-old cancer survivors had roughly the same cumulative incidence of grade 3 to 5 health conditions (19.6%) as the 50-year-old siblings (19.8%).

Overall, these findings highlight the importance of lifelong, risk-based healthcare for childhood cancer survivors, Dr Armstrong said. Depending on their cancer treatment and other risk factors, follow-up care may include performing health checks at a younger age than is recommended for the general public.

This study involved survivors whose cancer was diagnosed between 1970 and 1986. The researchers are now studying the health of adult cancer survivors from a more recent treatment era.

Doctor consulting with a

cancer patient and her father

Credit: Rhoda Baer

The “health gap” between childhood cancer survivors and their siblings widens with age, according to a study published in the Journal of Clinical Oncology.

Cancer survivors aged 20 to 34 years old were 3.8 times more likely than siblings of the same age to develop new cancers and other serious health conditions.

By age 35 and beyond, survivors had a 5-fold greater risk.

“Survivors remain at risk for serious health problems into their 40s and 50s, decades after they have completed treatment for childhood cancer,” said study author Gregory Armstrong, MD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.

“In fact, for survivors, the risk of illness and death increases significantly beyond the age of 35. Their siblings don’t share these same risks.”

Dr Armstrong and his colleagues uncovered these results by analyzing data from the Childhood Cancer Survivor Study, which included 14,359 survivors and 4301 healthy siblings.

The patients had been diagnosed with leukemias, lymphomas, and other pediatric cancers before age 21 and were followed for a median of 24.5 years (range, 5 to 39.3 years).

The researchers compared survivors to age-matched siblings, evaluating the incidence of severe, disabling, life-threatening, or fatal health conditions. This included new malignancies as well as diseases of the heart, lungs, liver, kidneys, and hormones.

The team found a heightened risk of these health conditions among cancer survivors. And that risk increased as the survivors aged.

At 20 years of age, 16% of survivors had serious health conditions, compared to 3.3% of siblings. But by age 50, the incidence had increased to 53.6% among survivors and 19.8% among siblings. At 50, 22.5% of survivors had at least 2 serious health problems, and 10.1% had 3 or more.

In a multivariate analysis, the hazard ratio for developing serious health conditions was significantly higher among survivors aged 35 and older than for those aged 20 to 34 (P=0.03).

Among survivors who reached age 35 without serious health problems, 25.9% developed a significant health problem in the next decade. In comparison, 6% of siblings developed their first serious health condition between the ages of 35 and 45.

In addition to showing a health gap between childhood cancer survivors and their siblings, this research adds to evidence that survivors experience accelerated aging. The 24-year-old cancer survivors had roughly the same cumulative incidence of grade 3 to 5 health conditions (19.6%) as the 50-year-old siblings (19.8%).

Overall, these findings highlight the importance of lifelong, risk-based healthcare for childhood cancer survivors, Dr Armstrong said. Depending on their cancer treatment and other risk factors, follow-up care may include performing health checks at a younger age than is recommended for the general public.

This study involved survivors whose cancer was diagnosed between 1970 and 1986. The researchers are now studying the health of adult cancer survivors from a more recent treatment era.

Nurse treating a cancer patient

Credit: Rhoda Baer

New research indicates that less than 2% of trials funded by the National Cancer Institute focus on racial and ethnic minorities, and minority participation in adult cancer trials is not representative of the US population.

The researchers said these findings suggest we must do more to promote minority-focused research and clinical trial recruitment, beyond the National Institutes of Health (NIH) Revitalization Act of 1993, which mandated the appropriate inclusion of minorities in all NIH-funded research.

“What is needed is deliberate effort,” said study author Moon Chen, Jr, PhD, of the University of California, Davis. “Minorities are not hard to reach. They are hardly reached.”

To assess minority inclusion in clinical trials, Dr Chen and his colleagues searched ClinicalTrials.gov, looking for trials sponsored by the National Cancer Institute that were available in January 2013.

They searched using terms for different minority groups, then counted the number of clinical trials with a primary focus on a particular ethnic or minority population. Roughly 150 trials out of 10,000—or less than 2%—met the criteria.

The researchers also reviewed abstracts and articles accessed from January through March 2013 on PubMed to find those that specifically examined minority accrual in clinical trials.

Of the 42 citations found, 5 included reports explicitly discussing participation levels by race and ethnicity. Those reports revealed an “encouraging but less than optimal” increase in specification of race or ethnicity in published results of clinical trials.

Dr Chen and his colleagues also reported that participation of adult minorities is not proportional to their representation in the US population.

For example, African Americans experience the highest cancer incidence of any racial group (593.7 cases per 100,000), but they have the lowest rates of cancer trial participation (tied with Hispanics), at 1.3%. It’s important to note, however, that clinical trial participation is low for all adult cancer patients, at 3% to 5%.

In contrast, the researchers pointed out that 60% of all patients under age 15 are enrolled in clinical trials. And minority representation among children is excellent, either equal to or greater than their proportion of the population.

To put the adult population on par with the pediatric population, researchers should design trials to include and focus on specific populations, Dr Chen said. Furthermore, scientific journals should insist on appropriate representation and analyses of NIH research by race and ethnicity.

“Whatever happens in the laboratory or in the clinic needs to be applied to solving real-world problems,” Dr Chen said. “And those relate to the disproportionate effects of cancer and other diseases on racial and ethnic minorities.”

Dr Chen and his colleagues reported this research in Cancer.

Nurse treating a cancer patient

Credit: Rhoda Baer

New research indicates that less than 2% of trials funded by the National Cancer Institute focus on racial and ethnic minorities, and minority participation in adult cancer trials is not representative of the US population.

The researchers said these findings suggest we must do more to promote minority-focused research and clinical trial recruitment, beyond the National Institutes of Health (NIH) Revitalization Act of 1993, which mandated the appropriate inclusion of minorities in all NIH-funded research.

“What is needed is deliberate effort,” said study author Moon Chen, Jr, PhD, of the University of California, Davis. “Minorities are not hard to reach. They are hardly reached.”

To assess minority inclusion in clinical trials, Dr Chen and his colleagues searched ClinicalTrials.gov, looking for trials sponsored by the National Cancer Institute that were available in January 2013.

They searched using terms for different minority groups, then counted the number of clinical trials with a primary focus on a particular ethnic or minority population. Roughly 150 trials out of 10,000—or less than 2%—met the criteria.

The researchers also reviewed abstracts and articles accessed from January through March 2013 on PubMed to find those that specifically examined minority accrual in clinical trials.

Of the 42 citations found, 5 included reports explicitly discussing participation levels by race and ethnicity. Those reports revealed an “encouraging but less than optimal” increase in specification of race or ethnicity in published results of clinical trials.

Dr Chen and his colleagues also reported that participation of adult minorities is not proportional to their representation in the US population.

For example, African Americans experience the highest cancer incidence of any racial group (593.7 cases per 100,000), but they have the lowest rates of cancer trial participation (tied with Hispanics), at 1.3%. It’s important to note, however, that clinical trial participation is low for all adult cancer patients, at 3% to 5%.

In contrast, the researchers pointed out that 60% of all patients under age 15 are enrolled in clinical trials. And minority representation among children is excellent, either equal to or greater than their proportion of the population.

To put the adult population on par with the pediatric population, researchers should design trials to include and focus on specific populations, Dr Chen said. Furthermore, scientific journals should insist on appropriate representation and analyses of NIH research by race and ethnicity.

“Whatever happens in the laboratory or in the clinic needs to be applied to solving real-world problems,” Dr Chen said. “And those relate to the disproportionate effects of cancer and other diseases on racial and ethnic minorities.”

Dr Chen and his colleagues reported this research in Cancer.

Nurse treating a cancer patient

Credit: Rhoda Baer

New research indicates that less than 2% of trials funded by the National Cancer Institute focus on racial and ethnic minorities, and minority participation in adult cancer trials is not representative of the US population.

The researchers said these findings suggest we must do more to promote minority-focused research and clinical trial recruitment, beyond the National Institutes of Health (NIH) Revitalization Act of 1993, which mandated the appropriate inclusion of minorities in all NIH-funded research.

“What is needed is deliberate effort,” said study author Moon Chen, Jr, PhD, of the University of California, Davis. “Minorities are not hard to reach. They are hardly reached.”

To assess minority inclusion in clinical trials, Dr Chen and his colleagues searched ClinicalTrials.gov, looking for trials sponsored by the National Cancer Institute that were available in January 2013.

They searched using terms for different minority groups, then counted the number of clinical trials with a primary focus on a particular ethnic or minority population. Roughly 150 trials out of 10,000—or less than 2%—met the criteria.

The researchers also reviewed abstracts and articles accessed from January through March 2013 on PubMed to find those that specifically examined minority accrual in clinical trials.

Of the 42 citations found, 5 included reports explicitly discussing participation levels by race and ethnicity. Those reports revealed an “encouraging but less than optimal” increase in specification of race or ethnicity in published results of clinical trials.

Dr Chen and his colleagues also reported that participation of adult minorities is not proportional to their representation in the US population.

For example, African Americans experience the highest cancer incidence of any racial group (593.7 cases per 100,000), but they have the lowest rates of cancer trial participation (tied with Hispanics), at 1.3%. It’s important to note, however, that clinical trial participation is low for all adult cancer patients, at 3% to 5%.

In contrast, the researchers pointed out that 60% of all patients under age 15 are enrolled in clinical trials. And minority representation among children is excellent, either equal to or greater than their proportion of the population.

To put the adult population on par with the pediatric population, researchers should design trials to include and focus on specific populations, Dr Chen said. Furthermore, scientific journals should insist on appropriate representation and analyses of NIH research by race and ethnicity.

“Whatever happens in the laboratory or in the clinic needs to be applied to solving real-world problems,” Dr Chen said. “And those relate to the disproportionate effects of cancer and other diseases on racial and ethnic minorities.”

Dr Chen and his colleagues reported this research in Cancer.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.