Lymphoma & Plasma Cell Disorders

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

James DeGregori, PhD

Photo courtesy of University

of Colorado Cancer Center

Oncogenesis does not depend only on the accumulation of mutations but on evolutionary pressures acting on cell populations, according to a paper published in PNAS.

The authors say the ecosystem of a healthy tissue landscape lets healthy cells outcompete cells with cancerous mutations.

It is when the tissue ecosystem changes due to aging, smoking, or other stressors that cells with cancerous mutations can suddenly find themselves the most fit.

And this allows the cell population to expand over generations of natural selection.

This model of oncogenesis has profound implications for cancer therapy and drug design, according to the authors.

“We’ve been trying to make drugs that target mutations in cancer cells,” said author James DeGregori, PhD, of University of Colorado School of Medicine in Aurora.

“But if it’s the ecosystem of the body, and not only cancer-causing mutations, that allows the growth of cancer, we should also be prioritizing interventions and lifestyle choices that promote the fitness of healthy cells in order to suppress the emergence of cancer.”

The proposed model helps to answer a long-standing question known as Peto’s Paradox. If cancer is due to random activating mutation, larger animals with more cells should be at greater risk of developing cancer earlier in their lives. Why then do mammals of vastly different sizes and lifespans all seem to develop cancer mostly late in life?

“Blue whales have more than a million times more cells and live about 50 times longer than a mouse, but the whale has no more risk than a mouse of developing cancer over its lifespan,” Dr DeGregori noted.

The answer he and colleague Andrii Rozhok, PhD, propose is that, in addition to activating mutations, cancer may require age-associated changes to the tissue landscape in order for evolution to favor the survival and growth of cancer cells over the competition of healthy cells.

“Healthy cells are optimized for the ecosystem of the healthy body,” Dr DeGregori said. “But when the tissue ecosystem changes, such as with aging or smoking, cancer-causing mutations are often very good at exploiting the conditions of a damaged tissue landscape.”

This model is supported by studies showing that mutations that can cause cancer do not necessarily increase a cell’s fitness.

“In fact, healthy cells are so optimized to the healthy tissue landscape that almost any mutation makes them less fit,” Dr DeGregori said.

For example, some cancer cells mutate in a way that allows them to survive in the oxygen-poor tissue environments found in the center of developing tumors. But this adaptation only confers a fitness benefit in oxygen-poor tissues.

In a healthy, oxygen-rich tissue, this mutation would not confer this advantage. In healthy tissue, cells with this mutation lose the evolutionary race to the healthy cells. Cancer cells are outcompeted and die, or, at least, their population is held in check and remains insignificantly small.

But what happens when the tissue landscape changes?

“When the body changes due to aging, smoking, inherited genetic differences, or other factors, it changes the tissue ecosystem, allowing a new kind of cell to replace the healthy ones,” Dr DeGregori said.

Certainly, cancer development requires mutations and other genetic alterations. But how do these mutations cause cancer?

It may not be that these mutations create accidental “super cells” that immediately run amok. Instead, it may be that oncogenic mutations are often or always present in the body but are kept at bay by selection pressures set against them.

That is, until the tissue ecosystem and its pressures change in ways that make cells with cancerous mutations more likely to survive than healthy cells. Over time, this allows the population of cancer cells to overcome that of healthy cells.

People can avoid some of these tissue changes by lifestyle choices, Dr DeGregori noted, but aging cannot be stopped. Still, there may be features of the tissue landscape that, with new therapies and new understanding, could be reinforced in ways to resist cancer better for longer.

Background The rates of depression in adults with cancer have been reported as high as 38%-58%. How depression affects overall health care expenditures in individuals with cancer is an under-researched area.

Objective To estimate excess average total health care expenditures associated with depression in adults with cancer by comparing those with and without depression after controlling for demographic, socioeconomic, access to care, and other health status variables.

Methods Cross-sectional data on 4,766 adult survivors of cancer from 2006-2009 of the nationally representative household survey, Medical Expenditure Panel Survey (MEPS), were used. The patients were older than 21 years. Cancer and depression were identified from the patients’ medical conditions files. Dependent variables consisted of total, inpatient, outpatient, emergency department, prescription drugs, and other expenditures. Ordinary least square (OLS) on logged dollars and generalized linear models with log-link function were performed. All analyses (SAS 9.3 and STATA12) accounted for the complex survey design of the MEPS.

Results Overall, 14% of individuals with cancer reported having depression. In those with cancer and depression, the average annual health care expenditures were $18,401 compared with $12,091 in those without depression. After adjusting for demographic, socioeconomic, access to care, and other health status variables, those with depression had about 31.7% greater total expenditures compared with those without depression. Total, outpatient, and prescription expenditures were higher in individuals with depression than in those without depression. Individuals with cancer and depression were significantly more likely to use emergency departments (adjusted odds ratio, 1.46) compared with their counterparts without depression.

Limitations Cancer patients who died during the reporting year were excluded. The financial burden of depression may have been underestimated because the costs of end-of-life care are high. The burden for each cancer type was not analyzed because of the small sample size.

Conclusion In adults with cancer, those with depression had higher health care utilization and expenditures compared with those without depression.

Funding/sponsorship One author partially supported by the National Institute of General Medical Sciences, U54GM104942.

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

Background The rates of depression in adults with cancer have been reported as high as 38%-58%. How depression affects overall health care expenditures in individuals with cancer is an under-researched area.

Objective To estimate excess average total health care expenditures associated with depression in adults with cancer by comparing those with and without depression after controlling for demographic, socioeconomic, access to care, and other health status variables.

Methods Cross-sectional data on 4,766 adult survivors of cancer from 2006-2009 of the nationally representative household survey, Medical Expenditure Panel Survey (MEPS), were used. The patients were older than 21 years. Cancer and depression were identified from the patients’ medical conditions files. Dependent variables consisted of total, inpatient, outpatient, emergency department, prescription drugs, and other expenditures. Ordinary least square (OLS) on logged dollars and generalized linear models with log-link function were performed. All analyses (SAS 9.3 and STATA12) accounted for the complex survey design of the MEPS.

Results Overall, 14% of individuals with cancer reported having depression. In those with cancer and depression, the average annual health care expenditures were $18,401 compared with $12,091 in those without depression. After adjusting for demographic, socioeconomic, access to care, and other health status variables, those with depression had about 31.7% greater total expenditures compared with those without depression. Total, outpatient, and prescription expenditures were higher in individuals with depression than in those without depression. Individuals with cancer and depression were significantly more likely to use emergency departments (adjusted odds ratio, 1.46) compared with their counterparts without depression.

Limitations Cancer patients who died during the reporting year were excluded. The financial burden of depression may have been underestimated because the costs of end-of-life care are high. The burden for each cancer type was not analyzed because of the small sample size.

Conclusion In adults with cancer, those with depression had higher health care utilization and expenditures compared with those without depression.

Funding/sponsorship One author partially supported by the National Institute of General Medical Sciences, U54GM104942.

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

Background The rates of depression in adults with cancer have been reported as high as 38%-58%. How depression affects overall health care expenditures in individuals with cancer is an under-researched area.

Objective To estimate excess average total health care expenditures associated with depression in adults with cancer by comparing those with and without depression after controlling for demographic, socioeconomic, access to care, and other health status variables.

Methods Cross-sectional data on 4,766 adult survivors of cancer from 2006-2009 of the nationally representative household survey, Medical Expenditure Panel Survey (MEPS), were used. The patients were older than 21 years. Cancer and depression were identified from the patients’ medical conditions files. Dependent variables consisted of total, inpatient, outpatient, emergency department, prescription drugs, and other expenditures. Ordinary least square (OLS) on logged dollars and generalized linear models with log-link function were performed. All analyses (SAS 9.3 and STATA12) accounted for the complex survey design of the MEPS.

Results Overall, 14% of individuals with cancer reported having depression. In those with cancer and depression, the average annual health care expenditures were $18,401 compared with $12,091 in those without depression. After adjusting for demographic, socioeconomic, access to care, and other health status variables, those with depression had about 31.7% greater total expenditures compared with those without depression. Total, outpatient, and prescription expenditures were higher in individuals with depression than in those without depression. Individuals with cancer and depression were significantly more likely to use emergency departments (adjusted odds ratio, 1.46) compared with their counterparts without depression.

Limitations Cancer patients who died during the reporting year were excluded. The financial burden of depression may have been underestimated because the costs of end-of-life care are high. The burden for each cancer type was not analyzed because of the small sample size.

Conclusion In adults with cancer, those with depression had higher health care utilization and expenditures compared with those without depression.

Funding/sponsorship One author partially supported by the National Institute of General Medical Sciences, U54GM104942.

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

Researcher in the lab

Photo by Darren Baker

A newly developed database may help physicians predict survival outcomes in patients with hematologic and solid tumor malignancies, according to a paper published in Nature Medicine.

The database, known as PRECOG, integrates gene expression patterns of 39 types of cancer from nearly 18,000 patients with data about how long those patients lived.

By combining these data, researchers were able to see broad patterns that correlate with survival. They also believe this information could help them pinpoint potential therapeutic targets for a range of cancers.

“We were able to identify key pathways that can dramatically stratify survival across diverse cancer types,” said Ash Alizadeh, MD, PhD, of Stanford University in California.

“The patterns were very striking, especially because few such examples are currently available for the use of genes or immune cells for cancer prognosis.”

In addition to identifying potentially useful gene expression patterns, the researchers used an analytical tool called CIBERSORT to determine the composition of leukocytes that flock to a tumor.

“We were able to infer which immune cells are present or absent in individual solid tumors, to estimate their prevalence, and to correlate that information with patient survival,” said Aaron Newman, PhD, of Stanford University.

“We found you can even broadly distinguish cancer types just based on what kind of immune cells have infiltrated the tumor.”

Compiling the data

Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.

“There are many more genes in a cell than there are patients with any one type of cancer, and this makes discovering the important genes for cancer outcomes a tough problem,” said Andrew Gentles, PhD, of Stanford University.

“Because it’s easy to find spurious associations that don’t hold up in follow-up studies, we combined information from a vast array of cancer types to better see meaningful correlations.”

The researchers first collected publicly available data on gene expression patterns of many types of cancers.

They then matched the gene expression profiles with clinical information about the patients, including their age, disease status, and how long they survived after diagnosis. Finally, the team combined the studies in a database.

“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” Dr Alizadeh said. “Then, we could ask what we could learn more broadly.”

Surprising findings

The researchers were surprised to find that prognostic genes were often shared among distinct cancer types, suggesting that similar biological programs impact survival across cancers.

They were able to identify the top 10 genes that seemed to confer adverse outcomes—FOXM1, BIRC5, TOP2A, TPX2, NME1, CCNB1, CEP55, TYMS, CENPF, and CDKN3—and the top 10 genes associated with more positive outcomes—KLRB1, ITM2B, CBX7, CD2, CREBL2, SATB1, NR3C1, TMEM66, KLRK1, and FUCA1.

Many of these genes are involved in aspects of cell division or are associated with distinct leukocytes that flood a tumor.

The researchers were also able to identify combinations of leukocytes that appear to be correlated with outcomes.

In particular, elevated numbers of plasma cells and certain types of T cells correlated with better patient survival rates across many different solid tumors. But a high proportion of granulocytes was associated with adverse outcomes.

The researchers hope that PRECOG and CIBERSORT will increase our understanding of cancer biology and aid the development of new therapies for cancer patients. The team is applying these tools to better predict which patients will respond to new and emerging anticancer therapies.

Dr Alizadeh said this is especially important given recent advances in the development of drugs that engage immune responses but work well only for a subset of cancer patients.

Researcher in the lab

Photo by Darren Baker

A newly developed database may help physicians predict survival outcomes in patients with hematologic and solid tumor malignancies, according to a paper published in Nature Medicine.

The database, known as PRECOG, integrates gene expression patterns of 39 types of cancer from nearly 18,000 patients with data about how long those patients lived.

By combining these data, researchers were able to see broad patterns that correlate with survival. They also believe this information could help them pinpoint potential therapeutic targets for a range of cancers.

“We were able to identify key pathways that can dramatically stratify survival across diverse cancer types,” said Ash Alizadeh, MD, PhD, of Stanford University in California.

“The patterns were very striking, especially because few such examples are currently available for the use of genes or immune cells for cancer prognosis.”

In addition to identifying potentially useful gene expression patterns, the researchers used an analytical tool called CIBERSORT to determine the composition of leukocytes that flock to a tumor.

“We were able to infer which immune cells are present or absent in individual solid tumors, to estimate their prevalence, and to correlate that information with patient survival,” said Aaron Newman, PhD, of Stanford University.

“We found you can even broadly distinguish cancer types just based on what kind of immune cells have infiltrated the tumor.”

Compiling the data

Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.

“There are many more genes in a cell than there are patients with any one type of cancer, and this makes discovering the important genes for cancer outcomes a tough problem,” said Andrew Gentles, PhD, of Stanford University.

“Because it’s easy to find spurious associations that don’t hold up in follow-up studies, we combined information from a vast array of cancer types to better see meaningful correlations.”

The researchers first collected publicly available data on gene expression patterns of many types of cancers.

They then matched the gene expression profiles with clinical information about the patients, including their age, disease status, and how long they survived after diagnosis. Finally, the team combined the studies in a database.

“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” Dr Alizadeh said. “Then, we could ask what we could learn more broadly.”

Surprising findings

The researchers were surprised to find that prognostic genes were often shared among distinct cancer types, suggesting that similar biological programs impact survival across cancers.

They were able to identify the top 10 genes that seemed to confer adverse outcomes—FOXM1, BIRC5, TOP2A, TPX2, NME1, CCNB1, CEP55, TYMS, CENPF, and CDKN3—and the top 10 genes associated with more positive outcomes—KLRB1, ITM2B, CBX7, CD2, CREBL2, SATB1, NR3C1, TMEM66, KLRK1, and FUCA1.

Many of these genes are involved in aspects of cell division or are associated with distinct leukocytes that flood a tumor.

The researchers were also able to identify combinations of leukocytes that appear to be correlated with outcomes.

In particular, elevated numbers of plasma cells and certain types of T cells correlated with better patient survival rates across many different solid tumors. But a high proportion of granulocytes was associated with adverse outcomes.

The researchers hope that PRECOG and CIBERSORT will increase our understanding of cancer biology and aid the development of new therapies for cancer patients. The team is applying these tools to better predict which patients will respond to new and emerging anticancer therapies.

Dr Alizadeh said this is especially important given recent advances in the development of drugs that engage immune responses but work well only for a subset of cancer patients.

Researcher in the lab

Photo by Darren Baker

A newly developed database may help physicians predict survival outcomes in patients with hematologic and solid tumor malignancies, according to a paper published in Nature Medicine.

The database, known as PRECOG, integrates gene expression patterns of 39 types of cancer from nearly 18,000 patients with data about how long those patients lived.

By combining these data, researchers were able to see broad patterns that correlate with survival. They also believe this information could help them pinpoint potential therapeutic targets for a range of cancers.

“We were able to identify key pathways that can dramatically stratify survival across diverse cancer types,” said Ash Alizadeh, MD, PhD, of Stanford University in California.

“The patterns were very striking, especially because few such examples are currently available for the use of genes or immune cells for cancer prognosis.”

In addition to identifying potentially useful gene expression patterns, the researchers used an analytical tool called CIBERSORT to determine the composition of leukocytes that flock to a tumor.

“We were able to infer which immune cells are present or absent in individual solid tumors, to estimate their prevalence, and to correlate that information with patient survival,” said Aaron Newman, PhD, of Stanford University.

“We found you can even broadly distinguish cancer types just based on what kind of immune cells have infiltrated the tumor.”

Compiling the data

Researchers have tried for years to identify specific patterns of gene expression in cancerous tumors that differ from those in normal tissue. But the extreme variability among individual patients and tumors has made the process difficult, even when focused on particular cancer types.

“There are many more genes in a cell than there are patients with any one type of cancer, and this makes discovering the important genes for cancer outcomes a tough problem,” said Andrew Gentles, PhD, of Stanford University.

“Because it’s easy to find spurious associations that don’t hold up in follow-up studies, we combined information from a vast array of cancer types to better see meaningful correlations.”

The researchers first collected publicly available data on gene expression patterns of many types of cancers.

They then matched the gene expression profiles with clinical information about the patients, including their age, disease status, and how long they survived after diagnosis. Finally, the team combined the studies in a database.

“We wanted to be able to connect gene expression data with patient outcome for thousands of people at once,” Dr Alizadeh said. “Then, we could ask what we could learn more broadly.”

Surprising findings

The researchers were surprised to find that prognostic genes were often shared among distinct cancer types, suggesting that similar biological programs impact survival across cancers.

They were able to identify the top 10 genes that seemed to confer adverse outcomes—FOXM1, BIRC5, TOP2A, TPX2, NME1, CCNB1, CEP55, TYMS, CENPF, and CDKN3—and the top 10 genes associated with more positive outcomes—KLRB1, ITM2B, CBX7, CD2, CREBL2, SATB1, NR3C1, TMEM66, KLRK1, and FUCA1.

Many of these genes are involved in aspects of cell division or are associated with distinct leukocytes that flood a tumor.

The researchers were also able to identify combinations of leukocytes that appear to be correlated with outcomes.

In particular, elevated numbers of plasma cells and certain types of T cells correlated with better patient survival rates across many different solid tumors. But a high proportion of granulocytes was associated with adverse outcomes.

The researchers hope that PRECOG and CIBERSORT will increase our understanding of cancer biology and aid the development of new therapies for cancer patients. The team is applying these tools to better predict which patients will respond to new and emerging anticancer therapies.

Dr Alizadeh said this is especially important given recent advances in the development of drugs that engage immune responses but work well only for a subset of cancer patients.

Micrograph showing DLBCL

Researchers say they have found evidence linking disrupted metabolism and diffuse large B-cell lymphoma (DLBCL).

“The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection—genetic mutations in metabolic enzymes,” said Ricardo C.T. Aguiar, MD, PhD, of the University of Texas Health Science Center at San Antonio.

“We have discovered a metabolic imbalance that is oncogenic or pro-cancer.”

Dr Aguiar and his colleagues described this discovery in Nature Communications.

The team found that the gene encoding the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in DLBCL.

The mutated lymphoma cell displays a deficiency of a metabolite called alpha-ketoglutarate (α-KG), which is needed in steady levels for cells to be healthy.

“When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don‘t function properly, resulting in a host of additional disturbances,” Dr Aguiar said.

He added that α-KG has been identified as a critical regulator of aging and stem cell maintenance. So the implications of his group’s findings are not limited to cancer biology.

Micrograph showing DLBCL

Researchers say they have found evidence linking disrupted metabolism and diffuse large B-cell lymphoma (DLBCL).

“The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection—genetic mutations in metabolic enzymes,” said Ricardo C.T. Aguiar, MD, PhD, of the University of Texas Health Science Center at San Antonio.

“We have discovered a metabolic imbalance that is oncogenic or pro-cancer.”

Dr Aguiar and his colleagues described this discovery in Nature Communications.

The team found that the gene encoding the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in DLBCL.

The mutated lymphoma cell displays a deficiency of a metabolite called alpha-ketoglutarate (α-KG), which is needed in steady levels for cells to be healthy.

“When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don‘t function properly, resulting in a host of additional disturbances,” Dr Aguiar said.

He added that α-KG has been identified as a critical regulator of aging and stem cell maintenance. So the implications of his group’s findings are not limited to cancer biology.

Micrograph showing DLBCL

Researchers say they have found evidence linking disrupted metabolism and diffuse large B-cell lymphoma (DLBCL).

“The link between metabolism and cancer has been proposed or inferred to exist for a long time, but what is more scarce is evidence for a direct connection—genetic mutations in metabolic enzymes,” said Ricardo C.T. Aguiar, MD, PhD, of the University of Texas Health Science Center at San Antonio.

“We have discovered a metabolic imbalance that is oncogenic or pro-cancer.”

Dr Aguiar and his colleagues described this discovery in Nature Communications.

The team found that the gene encoding the enzyme D2-hydroxyglutarate dehydrogenase (D2HGDH) is mutated in DLBCL.

The mutated lymphoma cell displays a deficiency of a metabolite called alpha-ketoglutarate (α-KG), which is needed in steady levels for cells to be healthy.

“When the levels of α-KG are abnormally low, another class of enzymes called dioxygenases don‘t function properly, resulting in a host of additional disturbances,” Dr Aguiar said.

He added that α-KG has been identified as a critical regulator of aging and stem cell maintenance. So the implications of his group’s findings are not limited to cancer biology.

Wyndham Wilson, MD, PhD

Photo by Larry Young

Responses to the BTK inhibitor ibrutinib differ according to a patient’s subtype of diffuse large B-cell lymphoma (DLBCL), results of a phase 1/2 trial suggest.

The study showed that patients with activated B-cell-like (ABC) DLBCL were more likely to respond to ibrutinib than patients with germinal center B-cell-like (GCB) DLBCL.

“This is the first clinical study to demonstrate the importance of precision medicine in lymphomas,” said Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.

Dr Wilson and his colleagues described the trial in Nature Medicine. The research, which was sponsored by Pharmacyclics, Inc. (the company developing ibrutinib), was previously presented at EHA 2013.

The trial enrolled 80 patients with relapsed or refractory DLBCL. All patients received ibrutinib. Tumor responses occurred in 25% of patients. There were 8 complete responses and 12 partial responses.

After a median follow-up of 11.5 months, the median progression-free survival was 1.6 months, and the median overall survival was 6.4 months.

An analysis of outcomes by disease subtype showed that ibrutinib produced complete or partial responses in 37% (14/38) of patients with ABC DLBCL but only 5% (1/20) of patients with GCB DLBCL.

The researchers speculated that ABC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, which would account for the sensitivity of ABC tumors to ibrutinib.

Based on this study’s results, researchers are conducting an international phase 3 trial of standard chemotherapy with or without ibrutinib in patients with DLBCL, excluding the GCB subtype (NCT01855750).

This is the first time a phase 3 trial has been designed to selectively enroll patients with a particular molecular subtype of DLBCL. The study’s objective is to determine if the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with ABC DLBCL.

Wyndham Wilson, MD, PhD

Photo by Larry Young

Responses to the BTK inhibitor ibrutinib differ according to a patient’s subtype of diffuse large B-cell lymphoma (DLBCL), results of a phase 1/2 trial suggest.

The study showed that patients with activated B-cell-like (ABC) DLBCL were more likely to respond to ibrutinib than patients with germinal center B-cell-like (GCB) DLBCL.

“This is the first clinical study to demonstrate the importance of precision medicine in lymphomas,” said Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.

Dr Wilson and his colleagues described the trial in Nature Medicine. The research, which was sponsored by Pharmacyclics, Inc. (the company developing ibrutinib), was previously presented at EHA 2013.

The trial enrolled 80 patients with relapsed or refractory DLBCL. All patients received ibrutinib. Tumor responses occurred in 25% of patients. There were 8 complete responses and 12 partial responses.

After a median follow-up of 11.5 months, the median progression-free survival was 1.6 months, and the median overall survival was 6.4 months.

An analysis of outcomes by disease subtype showed that ibrutinib produced complete or partial responses in 37% (14/38) of patients with ABC DLBCL but only 5% (1/20) of patients with GCB DLBCL.

The researchers speculated that ABC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, which would account for the sensitivity of ABC tumors to ibrutinib.

Based on this study’s results, researchers are conducting an international phase 3 trial of standard chemotherapy with or without ibrutinib in patients with DLBCL, excluding the GCB subtype (NCT01855750).

This is the first time a phase 3 trial has been designed to selectively enroll patients with a particular molecular subtype of DLBCL. The study’s objective is to determine if the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with ABC DLBCL.

Wyndham Wilson, MD, PhD

Photo by Larry Young

Responses to the BTK inhibitor ibrutinib differ according to a patient’s subtype of diffuse large B-cell lymphoma (DLBCL), results of a phase 1/2 trial suggest.

The study showed that patients with activated B-cell-like (ABC) DLBCL were more likely to respond to ibrutinib than patients with germinal center B-cell-like (GCB) DLBCL.

“This is the first clinical study to demonstrate the importance of precision medicine in lymphomas,” said Wyndham Wilson, MD, PhD, of the National Cancer Institute in Bethesda, Maryland.

Dr Wilson and his colleagues described the trial in Nature Medicine. The research, which was sponsored by Pharmacyclics, Inc. (the company developing ibrutinib), was previously presented at EHA 2013.

The trial enrolled 80 patients with relapsed or refractory DLBCL. All patients received ibrutinib. Tumor responses occurred in 25% of patients. There were 8 complete responses and 12 partial responses.

After a median follow-up of 11.5 months, the median progression-free survival was 1.6 months, and the median overall survival was 6.4 months.

An analysis of outcomes by disease subtype showed that ibrutinib produced complete or partial responses in 37% (14/38) of patients with ABC DLBCL but only 5% (1/20) of patients with GCB DLBCL.

The researchers speculated that ABC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, which would account for the sensitivity of ABC tumors to ibrutinib.

Based on this study’s results, researchers are conducting an international phase 3 trial of standard chemotherapy with or without ibrutinib in patients with DLBCL, excluding the GCB subtype (NCT01855750).

This is the first time a phase 3 trial has been designed to selectively enroll patients with a particular molecular subtype of DLBCL. The study’s objective is to determine if the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with ABC DLBCL.

Patient receiving chemotherapy

Photo by Rhoda Baer

New research suggests the polyphenols resveratrol and quercetin could be used to augment treatment with the anthracycline doxorubicin.

Investigators found they could increase the bioavailability of resveratrol and quercetin using copolymers that make the compounds water soluble and allow for their injection into the blood stream.

The team then showed the compounds synergize with doxorubicin while also reducing cardiac toxicity.

Although doxorubicin has proven effective against lymphomas, leukemias, and other cancers, the drug can only be used for a limited time because it confers cardiotoxicity.

The co-administration of resveratrol and quercetin might allow for much more extensive use of doxorubicin, while at the same time improving its efficacy and demonstrating the polyphenols’ own anticancer properties, investigators said.

They described research supporting this idea in the Journal of Controlled Release.

“This has great potential to improve chemotherapeutic cancer treatment,” said Adam Alani, PhD, of Oregon State University in Portland.

“The co-administration of high levels of resveratrol and quercetin, in both in vitro and in vivo studies, shows that it significantly reduces the cardiac toxicity of [doxorubicin]. And these compounds have a synergistic effect that enhances the efficacy of the cancer drug, by sensitizing the cancer cells to the effects of the drug.”

Dr Alani said further research may demonstrate that these compounds can completely eliminate the cardiotoxicity of doxorubicin, as they scavenge the toxic free radicals produced by this drug.

It’s also possible, he said, that administration of these natural polyphenols could have value in cancer therapy by themselves or in combination with a wider range of other chemotherapeutic drugs.

Increasing bioavailability

Resveratrol is a natural compound found in foods such as grapes, red wine, green tea, berries, and dark chocolate. Quercetin reaches some of its highest natural levels in capers, some berries, and leafy greens.

When consumed via food or taken as supplements, these polyphenol compounds reach only a tiny fraction of the level that’s possible with direct injection. Such injection was not possible until Dr Alani and his colleagues adapted the use of polymeric micelles.

Specifically, the investigators combined resveratrol and quercetin in Pluronic F127 micelles (mRQ). Pluronics are triblock copolymers consisting of a polypropylene oxide chain flanked with 2 polyethylene oxide chains that can self-assemble into polymeric micelles. The micelles have hydrophobic cores that help solubilize compounds with poor aqueous solubility.

“There are several advantages with this system,” Dr Alani said. “We can finally reach clinical levels of these polyphenols in the body. We can load both the compounds at one time to help control the cardiotoxicity of the cancer drug, and we can help the polyphenols accumulate in cancer cells where they have their own anticancer properties.”

In combination with doxorubicin

The investigators prepared mRQ micelles that were capable of retaining 1.1 mg/mL of resveratrol and 1.42 mg/mL of quercetin. They then tested mRQ in combination with doxorubicin in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2).

The team found that a resveratrol-quercetin-doxorubicin ratio of 10:10:1 was synergistic in SKOV-3 cells and antagonistic in H9C2 cells.

mRQ did not interfere with doxorubicin’s caspase activity in SKOV-3 cells but significantly decreased the activity in H9C2 cells. Likewise, there were no changes in the generation of reactive oxygen species in SKOV-3 cells, but there was significant scavenging in H9C2 cells.

The investigators also administered doxorubicin, with or without mRQ, to healthy mice and found that mRQ “conferred full cardioprotection.”

Dr Alani noted that previous research suggested resveratrol and quercetin are safe when given at high concentrations, but additional research is needed.

Patient receiving chemotherapy

Photo by Rhoda Baer

New research suggests the polyphenols resveratrol and quercetin could be used to augment treatment with the anthracycline doxorubicin.

Investigators found they could increase the bioavailability of resveratrol and quercetin using copolymers that make the compounds water soluble and allow for their injection into the blood stream.

The team then showed the compounds synergize with doxorubicin while also reducing cardiac toxicity.

Although doxorubicin has proven effective against lymphomas, leukemias, and other cancers, the drug can only be used for a limited time because it confers cardiotoxicity.

The co-administration of resveratrol and quercetin might allow for much more extensive use of doxorubicin, while at the same time improving its efficacy and demonstrating the polyphenols’ own anticancer properties, investigators said.

They described research supporting this idea in the Journal of Controlled Release.

“This has great potential to improve chemotherapeutic cancer treatment,” said Adam Alani, PhD, of Oregon State University in Portland.

“The co-administration of high levels of resveratrol and quercetin, in both in vitro and in vivo studies, shows that it significantly reduces the cardiac toxicity of [doxorubicin]. And these compounds have a synergistic effect that enhances the efficacy of the cancer drug, by sensitizing the cancer cells to the effects of the drug.”

Dr Alani said further research may demonstrate that these compounds can completely eliminate the cardiotoxicity of doxorubicin, as they scavenge the toxic free radicals produced by this drug.

It’s also possible, he said, that administration of these natural polyphenols could have value in cancer therapy by themselves or in combination with a wider range of other chemotherapeutic drugs.

Increasing bioavailability

Resveratrol is a natural compound found in foods such as grapes, red wine, green tea, berries, and dark chocolate. Quercetin reaches some of its highest natural levels in capers, some berries, and leafy greens.

When consumed via food or taken as supplements, these polyphenol compounds reach only a tiny fraction of the level that’s possible with direct injection. Such injection was not possible until Dr Alani and his colleagues adapted the use of polymeric micelles.

Specifically, the investigators combined resveratrol and quercetin in Pluronic F127 micelles (mRQ). Pluronics are triblock copolymers consisting of a polypropylene oxide chain flanked with 2 polyethylene oxide chains that can self-assemble into polymeric micelles. The micelles have hydrophobic cores that help solubilize compounds with poor aqueous solubility.

“There are several advantages with this system,” Dr Alani said. “We can finally reach clinical levels of these polyphenols in the body. We can load both the compounds at one time to help control the cardiotoxicity of the cancer drug, and we can help the polyphenols accumulate in cancer cells where they have their own anticancer properties.”

In combination with doxorubicin

The investigators prepared mRQ micelles that were capable of retaining 1.1 mg/mL of resveratrol and 1.42 mg/mL of quercetin. They then tested mRQ in combination with doxorubicin in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2).

The team found that a resveratrol-quercetin-doxorubicin ratio of 10:10:1 was synergistic in SKOV-3 cells and antagonistic in H9C2 cells.

mRQ did not interfere with doxorubicin’s caspase activity in SKOV-3 cells but significantly decreased the activity in H9C2 cells. Likewise, there were no changes in the generation of reactive oxygen species in SKOV-3 cells, but there was significant scavenging in H9C2 cells.

The investigators also administered doxorubicin, with or without mRQ, to healthy mice and found that mRQ “conferred full cardioprotection.”

Dr Alani noted that previous research suggested resveratrol and quercetin are safe when given at high concentrations, but additional research is needed.

Patient receiving chemotherapy

Photo by Rhoda Baer

New research suggests the polyphenols resveratrol and quercetin could be used to augment treatment with the anthracycline doxorubicin.

Investigators found they could increase the bioavailability of resveratrol and quercetin using copolymers that make the compounds water soluble and allow for their injection into the blood stream.

The team then showed the compounds synergize with doxorubicin while also reducing cardiac toxicity.

Although doxorubicin has proven effective against lymphomas, leukemias, and other cancers, the drug can only be used for a limited time because it confers cardiotoxicity.

The co-administration of resveratrol and quercetin might allow for much more extensive use of doxorubicin, while at the same time improving its efficacy and demonstrating the polyphenols’ own anticancer properties, investigators said.

They described research supporting this idea in the Journal of Controlled Release.

“This has great potential to improve chemotherapeutic cancer treatment,” said Adam Alani, PhD, of Oregon State University in Portland.

“The co-administration of high levels of resveratrol and quercetin, in both in vitro and in vivo studies, shows that it significantly reduces the cardiac toxicity of [doxorubicin]. And these compounds have a synergistic effect that enhances the efficacy of the cancer drug, by sensitizing the cancer cells to the effects of the drug.”

Dr Alani said further research may demonstrate that these compounds can completely eliminate the cardiotoxicity of doxorubicin, as they scavenge the toxic free radicals produced by this drug.

It’s also possible, he said, that administration of these natural polyphenols could have value in cancer therapy by themselves or in combination with a wider range of other chemotherapeutic drugs.

Increasing bioavailability

Resveratrol is a natural compound found in foods such as grapes, red wine, green tea, berries, and dark chocolate. Quercetin reaches some of its highest natural levels in capers, some berries, and leafy greens.

When consumed via food or taken as supplements, these polyphenol compounds reach only a tiny fraction of the level that’s possible with direct injection. Such injection was not possible until Dr Alani and his colleagues adapted the use of polymeric micelles.

Specifically, the investigators combined resveratrol and quercetin in Pluronic F127 micelles (mRQ). Pluronics are triblock copolymers consisting of a polypropylene oxide chain flanked with 2 polyethylene oxide chains that can self-assemble into polymeric micelles. The micelles have hydrophobic cores that help solubilize compounds with poor aqueous solubility.

“There are several advantages with this system,” Dr Alani said. “We can finally reach clinical levels of these polyphenols in the body. We can load both the compounds at one time to help control the cardiotoxicity of the cancer drug, and we can help the polyphenols accumulate in cancer cells where they have their own anticancer properties.”

In combination with doxorubicin

The investigators prepared mRQ micelles that were capable of retaining 1.1 mg/mL of resveratrol and 1.42 mg/mL of quercetin. They then tested mRQ in combination with doxorubicin in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2).

The team found that a resveratrol-quercetin-doxorubicin ratio of 10:10:1 was synergistic in SKOV-3 cells and antagonistic in H9C2 cells.

mRQ did not interfere with doxorubicin’s caspase activity in SKOV-3 cells but significantly decreased the activity in H9C2 cells. Likewise, there were no changes in the generation of reactive oxygen species in SKOV-3 cells, but there was significant scavenging in H9C2 cells.

The investigators also administered doxorubicin, with or without mRQ, to healthy mice and found that mRQ “conferred full cardioprotection.”

Dr Alani noted that previous research suggested resveratrol and quercetin are safe when given at high concentrations, but additional research is needed.

 

 

Pregnant woman

Photo by Nina Matthews

 

Researchers have again found evidence to suggest that tests used to identify chromosomal fetal disorders can detect occult malignancies in pregnant women.

In a study made public last month, non-invasive prenatal tests (NIPTs) revealed 2 cases of lymphoma and a case of ovarian cancer in expectant mothers.

In the new study, researchers showed that positive NIPT results were due to leukemia, lymphoma, or solid tumors in 10 expectant mothers.

The research was published in JAMA and presented at the 19th International Conference on Prenatal Diagnosis and Therapy in Washington, DC. Funding for the study was provided by Illumina, and company employees were involved in the research.

“We did this study because noninvasive prenatal testing using sequencing of cell-free DNA in the mother’s plasma is the fastest-growing area of prenatal testing and, indeed, of genomic medicine,” said study author Diana W. Bianchi, MD, of Tufts Medical Center in Boston, Massachusetts.

“As the volume of tests has expanded, we’ve become increasingly aware of the so-called “false-positive” cases. [A]pproximately 0.2% of the time, there is a discrepancy between the results of the prenatal test—in which an aneuploidy is reported—and the result from the diagnostic fetal procedure, the amniocentesis or the chorionic villus sampling.”

“So we’re interested in the situation where the fetal chromosomes are normal, but the prenatal test shows that there’s an aneuploidy detected. We’re interested in the possible explanations for that discrepancy.”

To gain some insight, Dr Bianchi and her colleagues evaluated 125,426 samples from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening using Illumina’s verifi Prenatal Test.

In all, 3757 samples (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. These were reported to the ordering physician with recommendations for further evaluation.

“In a small minority of women, [subsequent tests analyzing only fetal DNA] showed that the fetal chromosomes were normal, and that disagreed with [results of the NIPT],” Dr Bianchi said. “We were examining whether cancer could explain the discrepancy between these two test results.”

The researchers found that 10 of the women with discordant test results were subsequently diagnosed with cancer. There were 3 cases of B-cell lymphoma and 1 case each of T-cell leukemia, Hodgkin lymphoma, unspecified adenocarcinoma, leiomyosarcoma, and neuroendocrine, colorectal, and anal carcinomas.

Dr Bianchi and her colleagues were able to obtain detailed clinical and sequencing data for 8 of these cases. In the other 2 cases (leiomyosarcoma and unspecified adenocarcinoma), the women were critically ill and were not approached about participating in the study.

The researchers found that maternal cancers most frequently occurred when the NIPT detected more than 1 aneuploidy. There were 7 known cancers among 39 cases of multiple aneuploidies by NIPT. In 1 case, blood was sampled after the patient completed treatment for colorectal cancer, and the abnormal pattern was no longer evident.

When the researchers examined additional genetic information for the women with cancer, they found unique patterns of nonspecific copy-number gains and losses across multiple chromosomes.

“[These women] had DNA imbalances all across the genome,” Dr Bianchi said. “The [NIPT] normally is only looking at DNA material from the chromosomes of clinical interest—chromosomes 13, 18, 21, X, and Y.”

“When we opened up their results to look at all of the chromosomes, there were multiple abnormalities in other places, such as chromosome 8, chromosome 6, etc. Each woman had a unique pattern that was abnormal in many places. This suggested that it was the tumor DNA that was being shed into her blood and was contributing to the abnormal pattern.”

Dr Bianchi stressed that the tumor DNA did not affect the babies. She said all were born healthy, although labor was induced early in one mother to facilitate her cancer treatment.

 

 

Pregnant woman

Photo by Nina Matthews

 

Researchers have again found evidence to suggest that tests used to identify chromosomal fetal disorders can detect occult malignancies in pregnant women.

In a study made public last month, non-invasive prenatal tests (NIPTs) revealed 2 cases of lymphoma and a case of ovarian cancer in expectant mothers.

In the new study, researchers showed that positive NIPT results were due to leukemia, lymphoma, or solid tumors in 10 expectant mothers.

The research was published in JAMA and presented at the 19th International Conference on Prenatal Diagnosis and Therapy in Washington, DC. Funding for the study was provided by Illumina, and company employees were involved in the research.

“We did this study because noninvasive prenatal testing using sequencing of cell-free DNA in the mother’s plasma is the fastest-growing area of prenatal testing and, indeed, of genomic medicine,” said study author Diana W. Bianchi, MD, of Tufts Medical Center in Boston, Massachusetts.

“As the volume of tests has expanded, we’ve become increasingly aware of the so-called “false-positive” cases. [A]pproximately 0.2% of the time, there is a discrepancy between the results of the prenatal test—in which an aneuploidy is reported—and the result from the diagnostic fetal procedure, the amniocentesis or the chorionic villus sampling.”

“So we’re interested in the situation where the fetal chromosomes are normal, but the prenatal test shows that there’s an aneuploidy detected. We’re interested in the possible explanations for that discrepancy.”

To gain some insight, Dr Bianchi and her colleagues evaluated 125,426 samples from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening using Illumina’s verifi Prenatal Test.

In all, 3757 samples (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. These were reported to the ordering physician with recommendations for further evaluation.

“In a small minority of women, [subsequent tests analyzing only fetal DNA] showed that the fetal chromosomes were normal, and that disagreed with [results of the NIPT],” Dr Bianchi said. “We were examining whether cancer could explain the discrepancy between these two test results.”

The researchers found that 10 of the women with discordant test results were subsequently diagnosed with cancer. There were 3 cases of B-cell lymphoma and 1 case each of T-cell leukemia, Hodgkin lymphoma, unspecified adenocarcinoma, leiomyosarcoma, and neuroendocrine, colorectal, and anal carcinomas.

Dr Bianchi and her colleagues were able to obtain detailed clinical and sequencing data for 8 of these cases. In the other 2 cases (leiomyosarcoma and unspecified adenocarcinoma), the women were critically ill and were not approached about participating in the study.

The researchers found that maternal cancers most frequently occurred when the NIPT detected more than 1 aneuploidy. There were 7 known cancers among 39 cases of multiple aneuploidies by NIPT. In 1 case, blood was sampled after the patient completed treatment for colorectal cancer, and the abnormal pattern was no longer evident.

When the researchers examined additional genetic information for the women with cancer, they found unique patterns of nonspecific copy-number gains and losses across multiple chromosomes.

“[These women] had DNA imbalances all across the genome,” Dr Bianchi said. “The [NIPT] normally is only looking at DNA material from the chromosomes of clinical interest—chromosomes 13, 18, 21, X, and Y.”

“When we opened up their results to look at all of the chromosomes, there were multiple abnormalities in other places, such as chromosome 8, chromosome 6, etc. Each woman had a unique pattern that was abnormal in many places. This suggested that it was the tumor DNA that was being shed into her blood and was contributing to the abnormal pattern.”

Dr Bianchi stressed that the tumor DNA did not affect the babies. She said all were born healthy, although labor was induced early in one mother to facilitate her cancer treatment.

 

 

Pregnant woman

Photo by Nina Matthews

 

Researchers have again found evidence to suggest that tests used to identify chromosomal fetal disorders can detect occult malignancies in pregnant women.

In a study made public last month, non-invasive prenatal tests (NIPTs) revealed 2 cases of lymphoma and a case of ovarian cancer in expectant mothers.

In the new study, researchers showed that positive NIPT results were due to leukemia, lymphoma, or solid tumors in 10 expectant mothers.

The research was published in JAMA and presented at the 19th International Conference on Prenatal Diagnosis and Therapy in Washington, DC. Funding for the study was provided by Illumina, and company employees were involved in the research.

“We did this study because noninvasive prenatal testing using sequencing of cell-free DNA in the mother’s plasma is the fastest-growing area of prenatal testing and, indeed, of genomic medicine,” said study author Diana W. Bianchi, MD, of Tufts Medical Center in Boston, Massachusetts.

“As the volume of tests has expanded, we’ve become increasingly aware of the so-called “false-positive” cases. [A]pproximately 0.2% of the time, there is a discrepancy between the results of the prenatal test—in which an aneuploidy is reported—and the result from the diagnostic fetal procedure, the amniocentesis or the chorionic villus sampling.”

“So we’re interested in the situation where the fetal chromosomes are normal, but the prenatal test shows that there’s an aneuploidy detected. We’re interested in the possible explanations for that discrepancy.”

To gain some insight, Dr Bianchi and her colleagues evaluated 125,426 samples from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening using Illumina’s verifi Prenatal Test.

In all, 3757 samples (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. These were reported to the ordering physician with recommendations for further evaluation.

“In a small minority of women, [subsequent tests analyzing only fetal DNA] showed that the fetal chromosomes were normal, and that disagreed with [results of the NIPT],” Dr Bianchi said. “We were examining whether cancer could explain the discrepancy between these two test results.”

The researchers found that 10 of the women with discordant test results were subsequently diagnosed with cancer. There were 3 cases of B-cell lymphoma and 1 case each of T-cell leukemia, Hodgkin lymphoma, unspecified adenocarcinoma, leiomyosarcoma, and neuroendocrine, colorectal, and anal carcinomas.

Dr Bianchi and her colleagues were able to obtain detailed clinical and sequencing data for 8 of these cases. In the other 2 cases (leiomyosarcoma and unspecified adenocarcinoma), the women were critically ill and were not approached about participating in the study.

The researchers found that maternal cancers most frequently occurred when the NIPT detected more than 1 aneuploidy. There were 7 known cancers among 39 cases of multiple aneuploidies by NIPT. In 1 case, blood was sampled after the patient completed treatment for colorectal cancer, and the abnormal pattern was no longer evident.

When the researchers examined additional genetic information for the women with cancer, they found unique patterns of nonspecific copy-number gains and losses across multiple chromosomes.

“[These women] had DNA imbalances all across the genome,” Dr Bianchi said. “The [NIPT] normally is only looking at DNA material from the chromosomes of clinical interest—chromosomes 13, 18, 21, X, and Y.”

“When we opened up their results to look at all of the chromosomes, there were multiple abnormalities in other places, such as chromosome 8, chromosome 6, etc. Each woman had a unique pattern that was abnormal in many places. This suggested that it was the tumor DNA that was being shed into her blood and was contributing to the abnormal pattern.”

Dr Bianchi stressed that the tumor DNA did not affect the babies. She said all were born healthy, although labor was induced early in one mother to facilitate her cancer treatment.

Nancy Baxter, MD, PhD

Photo courtesy of

St. Michael’s Hospital

Up to 20 years after they are declared cancer-free, young adult (YA) cancer survivors are still hospitalized more often than the general population, according to research published in the Journal of Clinical Oncology.

Overall, the cancer survivors, who were ages 20 to 44 at diagnosis, were hospitalized about 1.5 times as often as control subjects.

“Even when young adults survive cancer, the cancer still has an impact on their lives and their long-term health, and this age group still has a lot of life to live,” said study author Nancy Baxter, MD, PhD, of St. Michael’s Hospital in Toronto, Ontario, Canada.

To conduct this study, Dr Baxter and her colleagues examined data from the Ontario Cancer Registry spanning the period from 1992 to 1999.

This included 20,275 patients who had their first cancer diagnosis between the ages of 20 and 44 and had lived for 5 years cancer-free. The researchers compared hospitalizations among these patients to hospitalizations in 101,344 non-cancer controls.

During the study period, 34.3% of cancer survivors (n=6948) were admitted to the hospital. The adjusted relative rate (ARR) of hospitalizations in survivors compared to controls was 1.51.

There was a significant decrease in hospitalizations among cancer survivors from the first time point the researchers analyzed to the last time point (P<0.0001).

But hospitalizations were more common among cancer survivors regardless of the time point. The ARR was 1.67 at 5 to 8 years after cancer diagnosis and 1.22 at 18 to 20 years after diagnosis.

When the researchers looked at individual malignancies, they found that survivors of melanoma or testicular cancer did not have higher rates of hospitalization than the control population. The ARRs were 0.97 and 1.07, respectively.

However, the rate of hospitalization was at least twice as high as the control population for survivors of leukemia (ARR=2.23) and lymphoma (ARR=2.02), as well as gastrointestinal (ARR=2.49), urologic (ARR=2.20), colorectal (ARR=2.10), and brain cancers (ARR=2.04).

Dr Baxter said having a better understanding of healthcare utilization and late effects in the YA cancer population may help healthcare providers counsel YA survivors on their future quality of life, identify areas where preventative strategies could be employed, and highlight the need to consider treatments that are not associated with long-term health consequences.

Nancy Baxter, MD, PhD

Photo courtesy of

St. Michael’s Hospital

Up to 20 years after they are declared cancer-free, young adult (YA) cancer survivors are still hospitalized more often than the general population, according to research published in the Journal of Clinical Oncology.

Overall, the cancer survivors, who were ages 20 to 44 at diagnosis, were hospitalized about 1.5 times as often as control subjects.

“Even when young adults survive cancer, the cancer still has an impact on their lives and their long-term health, and this age group still has a lot of life to live,” said study author Nancy Baxter, MD, PhD, of St. Michael’s Hospital in Toronto, Ontario, Canada.

To conduct this study, Dr Baxter and her colleagues examined data from the Ontario Cancer Registry spanning the period from 1992 to 1999.

This included 20,275 patients who had their first cancer diagnosis between the ages of 20 and 44 and had lived for 5 years cancer-free. The researchers compared hospitalizations among these patients to hospitalizations in 101,344 non-cancer controls.

During the study period, 34.3% of cancer survivors (n=6948) were admitted to the hospital. The adjusted relative rate (ARR) of hospitalizations in survivors compared to controls was 1.51.

There was a significant decrease in hospitalizations among cancer survivors from the first time point the researchers analyzed to the last time point (P<0.0001).

But hospitalizations were more common among cancer survivors regardless of the time point. The ARR was 1.67 at 5 to 8 years after cancer diagnosis and 1.22 at 18 to 20 years after diagnosis.

When the researchers looked at individual malignancies, they found that survivors of melanoma or testicular cancer did not have higher rates of hospitalization than the control population. The ARRs were 0.97 and 1.07, respectively.

However, the rate of hospitalization was at least twice as high as the control population for survivors of leukemia (ARR=2.23) and lymphoma (ARR=2.02), as well as gastrointestinal (ARR=2.49), urologic (ARR=2.20), colorectal (ARR=2.10), and brain cancers (ARR=2.04).

Dr Baxter said having a better understanding of healthcare utilization and late effects in the YA cancer population may help healthcare providers counsel YA survivors on their future quality of life, identify areas where preventative strategies could be employed, and highlight the need to consider treatments that are not associated with long-term health consequences.

Nancy Baxter, MD, PhD

Photo courtesy of

St. Michael’s Hospital

Up to 20 years after they are declared cancer-free, young adult (YA) cancer survivors are still hospitalized more often than the general population, according to research published in the Journal of Clinical Oncology.

Overall, the cancer survivors, who were ages 20 to 44 at diagnosis, were hospitalized about 1.5 times as often as control subjects.

“Even when young adults survive cancer, the cancer still has an impact on their lives and their long-term health, and this age group still has a lot of life to live,” said study author Nancy Baxter, MD, PhD, of St. Michael’s Hospital in Toronto, Ontario, Canada.

To conduct this study, Dr Baxter and her colleagues examined data from the Ontario Cancer Registry spanning the period from 1992 to 1999.

This included 20,275 patients who had their first cancer diagnosis between the ages of 20 and 44 and had lived for 5 years cancer-free. The researchers compared hospitalizations among these patients to hospitalizations in 101,344 non-cancer controls.

During the study period, 34.3% of cancer survivors (n=6948) were admitted to the hospital. The adjusted relative rate (ARR) of hospitalizations in survivors compared to controls was 1.51.

There was a significant decrease in hospitalizations among cancer survivors from the first time point the researchers analyzed to the last time point (P<0.0001).

But hospitalizations were more common among cancer survivors regardless of the time point. The ARR was 1.67 at 5 to 8 years after cancer diagnosis and 1.22 at 18 to 20 years after diagnosis.

When the researchers looked at individual malignancies, they found that survivors of melanoma or testicular cancer did not have higher rates of hospitalization than the control population. The ARRs were 0.97 and 1.07, respectively.

However, the rate of hospitalization was at least twice as high as the control population for survivors of leukemia (ARR=2.23) and lymphoma (ARR=2.02), as well as gastrointestinal (ARR=2.49), urologic (ARR=2.20), colorectal (ARR=2.10), and brain cancers (ARR=2.04).

Dr Baxter said having a better understanding of healthcare utilization and late effects in the YA cancer population may help healthcare providers counsel YA survivors on their future quality of life, identify areas where preventative strategies could be employed, and highlight the need to consider treatments that are not associated with long-term health consequences.