HT Staff

Cancer patient receives therapy

Credit: Rhoda Baer

The first reported outbreak of Tsukamurella species bloodstream infections was due to improper handling of intravenous saline, according to a report published in Infection Control and Hospital Epidemiology.

From September 2011 to May 2012, 15 immunocompromised patients treated at an outpatient oncology clinic in West Virginia developed infections with Tsukamurella, which are gram-positive bacteria that rarely cause disease in humans.

All patients had received a cancer diagnosis and had an indwelling central line, although central line types varied.

A case-control study revealed that the only risk factor for developing Tsukamurella infection was the receipt of a saline flush in September or October 2011, when clinic staff were using a common-source bag of saline.

Investigations by the West Virginia Bureau of Public Health (WVBPH) and the Centers for Disease Control and Prevention (CDC) uncovered several lapses in infection control procedures relating to the care of long-term intravenous catheters and preparation of chemotherapy for patients at the clinic.

However, these investigations also suggested that saline flush syringes were the likely source of infection.

So the WVBPH and the CDC recommended the clinic institute several changes to its infection prevention and control practices, including using pre-packaged, manufactured saline flushes.

After the clinic changed this practice, Tsukamurella bloodstream infections stopped occurring, further supporting the saline flush as the source of infection.

“This outbreak illustrates the need for outpatient clinics to follow proper infection control guidelines and medication preparation practices to minimize the risk of infection for patients with weakened immune systems,” said lead study author Isaac See, MD, of the CDC.

To that end, the CDC has developed a basic infection control plan tailored to outpatient oncology facilities.

The plan outlines policies and procedures needed to meet minimal requirements for patient safety, including the proper use and handling of injectable medications and correct procedures for assessing central lines.

Cancer patient receives therapy

Credit: Rhoda Baer

The first reported outbreak of Tsukamurella species bloodstream infections was due to improper handling of intravenous saline, according to a report published in Infection Control and Hospital Epidemiology.

From September 2011 to May 2012, 15 immunocompromised patients treated at an outpatient oncology clinic in West Virginia developed infections with Tsukamurella, which are gram-positive bacteria that rarely cause disease in humans.

All patients had received a cancer diagnosis and had an indwelling central line, although central line types varied.

A case-control study revealed that the only risk factor for developing Tsukamurella infection was the receipt of a saline flush in September or October 2011, when clinic staff were using a common-source bag of saline.

Investigations by the West Virginia Bureau of Public Health (WVBPH) and the Centers for Disease Control and Prevention (CDC) uncovered several lapses in infection control procedures relating to the care of long-term intravenous catheters and preparation of chemotherapy for patients at the clinic.

However, these investigations also suggested that saline flush syringes were the likely source of infection.

So the WVBPH and the CDC recommended the clinic institute several changes to its infection prevention and control practices, including using pre-packaged, manufactured saline flushes.

After the clinic changed this practice, Tsukamurella bloodstream infections stopped occurring, further supporting the saline flush as the source of infection.

“This outbreak illustrates the need for outpatient clinics to follow proper infection control guidelines and medication preparation practices to minimize the risk of infection for patients with weakened immune systems,” said lead study author Isaac See, MD, of the CDC.

To that end, the CDC has developed a basic infection control plan tailored to outpatient oncology facilities.

The plan outlines policies and procedures needed to meet minimal requirements for patient safety, including the proper use and handling of injectable medications and correct procedures for assessing central lines.

Cancer patient receives therapy

Credit: Rhoda Baer

The first reported outbreak of Tsukamurella species bloodstream infections was due to improper handling of intravenous saline, according to a report published in Infection Control and Hospital Epidemiology.

From September 2011 to May 2012, 15 immunocompromised patients treated at an outpatient oncology clinic in West Virginia developed infections with Tsukamurella, which are gram-positive bacteria that rarely cause disease in humans.

All patients had received a cancer diagnosis and had an indwelling central line, although central line types varied.

A case-control study revealed that the only risk factor for developing Tsukamurella infection was the receipt of a saline flush in September or October 2011, when clinic staff were using a common-source bag of saline.

Investigations by the West Virginia Bureau of Public Health (WVBPH) and the Centers for Disease Control and Prevention (CDC) uncovered several lapses in infection control procedures relating to the care of long-term intravenous catheters and preparation of chemotherapy for patients at the clinic.

However, these investigations also suggested that saline flush syringes were the likely source of infection.

So the WVBPH and the CDC recommended the clinic institute several changes to its infection prevention and control practices, including using pre-packaged, manufactured saline flushes.

After the clinic changed this practice, Tsukamurella bloodstream infections stopped occurring, further supporting the saline flush as the source of infection.

“This outbreak illustrates the need for outpatient clinics to follow proper infection control guidelines and medication preparation practices to minimize the risk of infection for patients with weakened immune systems,” said lead study author Isaac See, MD, of the CDC.

To that end, the CDC has developed a basic infection control plan tailored to outpatient oncology facilities.

The plan outlines policies and procedures needed to meet minimal requirements for patient safety, including the proper use and handling of injectable medications and correct procedures for assessing central lines.

Lab mice

Credit: Aaron Logan

Two papers published in Nature Immunology have shed new light on the role of Ikaros in B-cell acute lymphoblastic leukemia (B-ALL).

In one paper, researchers describe experiments in mice that show a defect in Ikaros function can disrupt lymphopoiesis and prevent the development of mature B cells.

The cells stay in an aberrant state, which closely resembles that of cells in human B-ALL.

The other paper provides insight into how pre-B cells transition from a proliferative phase to a differentiation phase.

Investigators found that this process, which is vulnerable to leukemic transformation, is dependent upon Ikaros.

Ikaros defect in mice mimics human B-ALL

In the first sudy, researchers showed that loss of Ikaros function in mice creates an environment that mimics human B-ALL.

“We already know several transcription factors that play a central role in B-cell differentiation,” said study author Meinrad Busslinger, PhD, of the Research Institute of Molecular Pathology in Vienna, Austria.

“Pax5, for example, represents a critical factor which activates the B-cell-specific program in precursor cells and simultaneously suppresses alternative cell fates. For Ikaros, we did not know, until now, what this factor is doing during early B-cell development.”

To find out, he and his colleagues analyzed mice that lacked Ikaros from an early stage of B-cell development on. They found that Ikaros deficiency arrested B-cell development due to a defect in pre-BCR signaling.

The cells remained in an aberrant, pro-B-cell stage and were prevented from further differentiation. They also showed increased cell adhesion and reduced migration compared to normal cells.

The researchers noted that loss of Ikaros function has previously been associated with the development of B-ALL. As in mice with a mutated Ikaros gene, B cells from B-ALL patients are arrested at an early checkpoint of B-cell development.

Loss of Ikaros in pre-B cells

With the second study, investigators provided new insight into pre-B-cell differentiation. They described the cells’ transition from a stroma-adherent proliferative phase to a nonadherent differentiation phase.

The stroma-adherent pre-B cells were highly proliferative and had limited self-renewing potential. But when they transitioned to the nonadherent phase, they exited the cell cycle, lost their capacity for self-renewal, and acquired the expression of genes encoding molecules that support B-cell maturation.

And this transition was dependent upon Ikaros.

“Loss of function in the transcription factor Ikaros appears to create a differentiation block that drives the pre-B cells into an adhesive state, promotes self-renewal, and primes them for malignant potential,” said study author Richard Van Etten, MD, PhD, of the University of California, Irvine.

Furthermore, the survival and proliferation of the Ikaros-deficient pre-B cells appeared to be dependent on cooperation between signaling via integrins and signaling via receptors for growth factors.

The researchers said this discovery points to a new avenue for treating B-ALLs resulting from Ikaros mutations.

Lab mice

Credit: Aaron Logan

Two papers published in Nature Immunology have shed new light on the role of Ikaros in B-cell acute lymphoblastic leukemia (B-ALL).

In one paper, researchers describe experiments in mice that show a defect in Ikaros function can disrupt lymphopoiesis and prevent the development of mature B cells.

The cells stay in an aberrant state, which closely resembles that of cells in human B-ALL.

The other paper provides insight into how pre-B cells transition from a proliferative phase to a differentiation phase.

Investigators found that this process, which is vulnerable to leukemic transformation, is dependent upon Ikaros.

Ikaros defect in mice mimics human B-ALL

In the first sudy, researchers showed that loss of Ikaros function in mice creates an environment that mimics human B-ALL.

“We already know several transcription factors that play a central role in B-cell differentiation,” said study author Meinrad Busslinger, PhD, of the Research Institute of Molecular Pathology in Vienna, Austria.

“Pax5, for example, represents a critical factor which activates the B-cell-specific program in precursor cells and simultaneously suppresses alternative cell fates. For Ikaros, we did not know, until now, what this factor is doing during early B-cell development.”

To find out, he and his colleagues analyzed mice that lacked Ikaros from an early stage of B-cell development on. They found that Ikaros deficiency arrested B-cell development due to a defect in pre-BCR signaling.

The cells remained in an aberrant, pro-B-cell stage and were prevented from further differentiation. They also showed increased cell adhesion and reduced migration compared to normal cells.

The researchers noted that loss of Ikaros function has previously been associated with the development of B-ALL. As in mice with a mutated Ikaros gene, B cells from B-ALL patients are arrested at an early checkpoint of B-cell development.

Loss of Ikaros in pre-B cells

With the second study, investigators provided new insight into pre-B-cell differentiation. They described the cells’ transition from a stroma-adherent proliferative phase to a nonadherent differentiation phase.

The stroma-adherent pre-B cells were highly proliferative and had limited self-renewing potential. But when they transitioned to the nonadherent phase, they exited the cell cycle, lost their capacity for self-renewal, and acquired the expression of genes encoding molecules that support B-cell maturation.

And this transition was dependent upon Ikaros.

“Loss of function in the transcription factor Ikaros appears to create a differentiation block that drives the pre-B cells into an adhesive state, promotes self-renewal, and primes them for malignant potential,” said study author Richard Van Etten, MD, PhD, of the University of California, Irvine.

Furthermore, the survival and proliferation of the Ikaros-deficient pre-B cells appeared to be dependent on cooperation between signaling via integrins and signaling via receptors for growth factors.

The researchers said this discovery points to a new avenue for treating B-ALLs resulting from Ikaros mutations.

Lab mice

Credit: Aaron Logan

Two papers published in Nature Immunology have shed new light on the role of Ikaros in B-cell acute lymphoblastic leukemia (B-ALL).

In one paper, researchers describe experiments in mice that show a defect in Ikaros function can disrupt lymphopoiesis and prevent the development of mature B cells.

The cells stay in an aberrant state, which closely resembles that of cells in human B-ALL.

The other paper provides insight into how pre-B cells transition from a proliferative phase to a differentiation phase.

Investigators found that this process, which is vulnerable to leukemic transformation, is dependent upon Ikaros.

Ikaros defect in mice mimics human B-ALL

In the first sudy, researchers showed that loss of Ikaros function in mice creates an environment that mimics human B-ALL.

“We already know several transcription factors that play a central role in B-cell differentiation,” said study author Meinrad Busslinger, PhD, of the Research Institute of Molecular Pathology in Vienna, Austria.

“Pax5, for example, represents a critical factor which activates the B-cell-specific program in precursor cells and simultaneously suppresses alternative cell fates. For Ikaros, we did not know, until now, what this factor is doing during early B-cell development.”

To find out, he and his colleagues analyzed mice that lacked Ikaros from an early stage of B-cell development on. They found that Ikaros deficiency arrested B-cell development due to a defect in pre-BCR signaling.

The cells remained in an aberrant, pro-B-cell stage and were prevented from further differentiation. They also showed increased cell adhesion and reduced migration compared to normal cells.

The researchers noted that loss of Ikaros function has previously been associated with the development of B-ALL. As in mice with a mutated Ikaros gene, B cells from B-ALL patients are arrested at an early checkpoint of B-cell development.

Loss of Ikaros in pre-B cells

With the second study, investigators provided new insight into pre-B-cell differentiation. They described the cells’ transition from a stroma-adherent proliferative phase to a nonadherent differentiation phase.

The stroma-adherent pre-B cells were highly proliferative and had limited self-renewing potential. But when they transitioned to the nonadherent phase, they exited the cell cycle, lost their capacity for self-renewal, and acquired the expression of genes encoding molecules that support B-cell maturation.

And this transition was dependent upon Ikaros.

“Loss of function in the transcription factor Ikaros appears to create a differentiation block that drives the pre-B cells into an adhesive state, promotes self-renewal, and primes them for malignant potential,” said study author Richard Van Etten, MD, PhD, of the University of California, Irvine.

Furthermore, the survival and proliferation of the Ikaros-deficient pre-B cells appeared to be dependent on cooperation between signaling via integrins and signaling via receptors for growth factors.

The researchers said this discovery points to a new avenue for treating B-ALLs resulting from Ikaros mutations.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Megakaryocytes

Researchers have linked a mutation causing Down syndrome-associated leukemias to developmental abnormalities in megakaryocytes.

Experiments showed that the leukemia-associated GATA1 mutant, GATA1s, interferes with the enzyme calpain 2, which acts as an initial trigger for a chain of reactions that determines the size and shape of megakaryocytes.

This interference hinders the normal process of cellular enlargement and platelet production.

“It’s like there’s a long pipeline and there’s a clog,” explained study author Adam N. Goldfarb, MD, of the University of Virginia School of Medicine in Charlottesville.

“We think it’s this pipeline that’s getting clogged in this disease and other diseases.”

Dr Goldfarb and his colleagues explained this discovery in Developmental Cell.

The researchers found that leukemia cells with the GATA1s mutation display a critical deficiency of calpain 2. And the enzyme’s absence leaves them stuck in an early stage of development, contributing to the development of Down syndrome-associated leukemias.

That could be the case in other forms of leukemia as well, Dr Goldfarb noted.

“These leukemias in Down syndrome aren’t that common,” he said, “but this finding has implications for other leukemias in that it lets us understand basic growth and development patterns.”

The team discovered that restoring calpain 2 expression in affected cells fixed the problem and allowed normal megakaryocyte development to resume.

As such, the researchers speculate that calpain deficiency could be a key defect in Down syndrome-associated leukemias, which provides a potential target for therapeutic development.

The findings might also help us find a way to mimic the natural process that allows a subset of Down syndrome-associated leukemias to disappear spontaneously.

Megakaryocytes

Researchers have linked a mutation causing Down syndrome-associated leukemias to developmental abnormalities in megakaryocytes.

Experiments showed that the leukemia-associated GATA1 mutant, GATA1s, interferes with the enzyme calpain 2, which acts as an initial trigger for a chain of reactions that determines the size and shape of megakaryocytes.

This interference hinders the normal process of cellular enlargement and platelet production.

“It’s like there’s a long pipeline and there’s a clog,” explained study author Adam N. Goldfarb, MD, of the University of Virginia School of Medicine in Charlottesville.

“We think it’s this pipeline that’s getting clogged in this disease and other diseases.”

Dr Goldfarb and his colleagues explained this discovery in Developmental Cell.

The researchers found that leukemia cells with the GATA1s mutation display a critical deficiency of calpain 2. And the enzyme’s absence leaves them stuck in an early stage of development, contributing to the development of Down syndrome-associated leukemias.

That could be the case in other forms of leukemia as well, Dr Goldfarb noted.

“These leukemias in Down syndrome aren’t that common,” he said, “but this finding has implications for other leukemias in that it lets us understand basic growth and development patterns.”

The team discovered that restoring calpain 2 expression in affected cells fixed the problem and allowed normal megakaryocyte development to resume.

As such, the researchers speculate that calpain deficiency could be a key defect in Down syndrome-associated leukemias, which provides a potential target for therapeutic development.

The findings might also help us find a way to mimic the natural process that allows a subset of Down syndrome-associated leukemias to disappear spontaneously.

Megakaryocytes

Researchers have linked a mutation causing Down syndrome-associated leukemias to developmental abnormalities in megakaryocytes.

Experiments showed that the leukemia-associated GATA1 mutant, GATA1s, interferes with the enzyme calpain 2, which acts as an initial trigger for a chain of reactions that determines the size and shape of megakaryocytes.

This interference hinders the normal process of cellular enlargement and platelet production.

“It’s like there’s a long pipeline and there’s a clog,” explained study author Adam N. Goldfarb, MD, of the University of Virginia School of Medicine in Charlottesville.

“We think it’s this pipeline that’s getting clogged in this disease and other diseases.”

Dr Goldfarb and his colleagues explained this discovery in Developmental Cell.

The researchers found that leukemia cells with the GATA1s mutation display a critical deficiency of calpain 2. And the enzyme’s absence leaves them stuck in an early stage of development, contributing to the development of Down syndrome-associated leukemias.

That could be the case in other forms of leukemia as well, Dr Goldfarb noted.

“These leukemias in Down syndrome aren’t that common,” he said, “but this finding has implications for other leukemias in that it lets us understand basic growth and development patterns.”

The team discovered that restoring calpain 2 expression in affected cells fixed the problem and allowed normal megakaryocyte development to resume.

As such, the researchers speculate that calpain deficiency could be a key defect in Down syndrome-associated leukemias, which provides a potential target for therapeutic development.

The findings might also help us find a way to mimic the natural process that allows a subset of Down syndrome-associated leukemias to disappear spontaneously.

Mother and son

Credit: George Hodan

Although they initially show signs of psychological distress, parents of children undergoing stem cell transplant (SCT) are as resilient as the children themselves, new research suggests.

Investigators evaluated psychological adjustment in 171 children undergoing SCT and their parents.

Results in the children, which were previously reported in Pediatrics, suggested they were well-adjusted after SCT, whether or not they had received therapy to promote psychological well-being.

Results in the parents, which are now available in Biology of Blood and Marrow Transplantation, are similar.

“The aim of the study was to examine an intervention to promote positive adjustment of patients and their parents,” said study author Jennifer Lindwall, PhD, of St Jude Children’s Research Hospital and Children’s Hospital of Colorado.

The 171 parent/child pairs were randomized to receive a child-targeted intervention, a child and parent intervention, or standard care. The child intervention consisted of massage and humor therapy, and the parent intervention included massage and relaxation/imagery training.

The investigators measured psychological distress and positive affect from the time of admission for a child’s SCT until 6 weeks after the procedure.

The team also measured depression, post-traumatic stress disorder (PTSD), and benefit-finding (potential positive outcomes that result from enduring a difficult experience) at the time of admission and 24 weeks after.

There were no significant differences among the 3 groups with regard to measures of parental distress. And distress decreased significantly from baseline to week 6.

Improvements also occurred over time with regard to positive affect. However, parents in the child/parent-intervention group and child-only-intervention group experienced significant benefits over the standard-care group.

On the other hand, there were no significant differences among the 3 groups with regard to depression, PTSD, and benefit-finding.

Parents from all groups experienced significant decreases in depression and PTSD from baseline to the 24-week mark. And they showed significant increases in benefit-finding.

“In many respects, a parent’s distress parallels the child’s distress,” Dr Lindwall said. “As things get better for the child, they get better for the parent as well.”

Dr Lindwall noted that, although this study suggests resiliency is the norm, there are parents who remain distressed as a result of their child’s illness.

“Our challenge now is to predict which parents are at the highest risk for difficulties,” she said, “and to design interventions that can help these parents cope during their child’s medical challenges.”

Mother and son

Credit: George Hodan

Although they initially show signs of psychological distress, parents of children undergoing stem cell transplant (SCT) are as resilient as the children themselves, new research suggests.

Investigators evaluated psychological adjustment in 171 children undergoing SCT and their parents.

Results in the children, which were previously reported in Pediatrics, suggested they were well-adjusted after SCT, whether or not they had received therapy to promote psychological well-being.

Results in the parents, which are now available in Biology of Blood and Marrow Transplantation, are similar.

“The aim of the study was to examine an intervention to promote positive adjustment of patients and their parents,” said study author Jennifer Lindwall, PhD, of St Jude Children’s Research Hospital and Children’s Hospital of Colorado.

The 171 parent/child pairs were randomized to receive a child-targeted intervention, a child and parent intervention, or standard care. The child intervention consisted of massage and humor therapy, and the parent intervention included massage and relaxation/imagery training.

The investigators measured psychological distress and positive affect from the time of admission for a child’s SCT until 6 weeks after the procedure.

The team also measured depression, post-traumatic stress disorder (PTSD), and benefit-finding (potential positive outcomes that result from enduring a difficult experience) at the time of admission and 24 weeks after.

There were no significant differences among the 3 groups with regard to measures of parental distress. And distress decreased significantly from baseline to week 6.

Improvements also occurred over time with regard to positive affect. However, parents in the child/parent-intervention group and child-only-intervention group experienced significant benefits over the standard-care group.

On the other hand, there were no significant differences among the 3 groups with regard to depression, PTSD, and benefit-finding.

Parents from all groups experienced significant decreases in depression and PTSD from baseline to the 24-week mark. And they showed significant increases in benefit-finding.

“In many respects, a parent’s distress parallels the child’s distress,” Dr Lindwall said. “As things get better for the child, they get better for the parent as well.”

Dr Lindwall noted that, although this study suggests resiliency is the norm, there are parents who remain distressed as a result of their child’s illness.

“Our challenge now is to predict which parents are at the highest risk for difficulties,” she said, “and to design interventions that can help these parents cope during their child’s medical challenges.”

Mother and son

Credit: George Hodan

Although they initially show signs of psychological distress, parents of children undergoing stem cell transplant (SCT) are as resilient as the children themselves, new research suggests.

Investigators evaluated psychological adjustment in 171 children undergoing SCT and their parents.

Results in the children, which were previously reported in Pediatrics, suggested they were well-adjusted after SCT, whether or not they had received therapy to promote psychological well-being.

Results in the parents, which are now available in Biology of Blood and Marrow Transplantation, are similar.

“The aim of the study was to examine an intervention to promote positive adjustment of patients and their parents,” said study author Jennifer Lindwall, PhD, of St Jude Children’s Research Hospital and Children’s Hospital of Colorado.

The 171 parent/child pairs were randomized to receive a child-targeted intervention, a child and parent intervention, or standard care. The child intervention consisted of massage and humor therapy, and the parent intervention included massage and relaxation/imagery training.

The investigators measured psychological distress and positive affect from the time of admission for a child’s SCT until 6 weeks after the procedure.

The team also measured depression, post-traumatic stress disorder (PTSD), and benefit-finding (potential positive outcomes that result from enduring a difficult experience) at the time of admission and 24 weeks after.

There were no significant differences among the 3 groups with regard to measures of parental distress. And distress decreased significantly from baseline to week 6.

Improvements also occurred over time with regard to positive affect. However, parents in the child/parent-intervention group and child-only-intervention group experienced significant benefits over the standard-care group.

On the other hand, there were no significant differences among the 3 groups with regard to depression, PTSD, and benefit-finding.

Parents from all groups experienced significant decreases in depression and PTSD from baseline to the 24-week mark. And they showed significant increases in benefit-finding.

“In many respects, a parent’s distress parallels the child’s distress,” Dr Lindwall said. “As things get better for the child, they get better for the parent as well.”

Dr Lindwall noted that, although this study suggests resiliency is the norm, there are parents who remain distressed as a result of their child’s illness.

“Our challenge now is to predict which parents are at the highest risk for difficulties,” she said, “and to design interventions that can help these parents cope during their child’s medical challenges.”

A new study has shown that hematopoietic stem cells (HSCs) can acquire mutations in DNMT3A, and this may be the first step in initiating acute myeloid leukemia (AML).

These HSCs also appear to be a means of treatment resistance and may trigger relapse in patients with AML, investigators reported in Nature.

“Our discovery lays the groundwork to detect and target the pre-leukemic stem cell and thereby potentially stop the disease at a very early stage, when it may be more amenable to treatment,” said study author John Dick, PhD, of the University of Toronto in Ontario, Canada.

“Now, we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse.”

Dr Dick and his colleagues analyzed 71 samples from AML patients and discovered that 17 of them (24%) carried mutations in DNMT3A. Fifteen of those samples (88%) also had mutated NPM1.

Both mutations were present in patients’ blasts. But 12 patients (70.5%) had T cells that contained DNMT3A mutations but no NPM1 mutations. FLT3-ITD mutations were also present in blasts but not T cells in 2 patients.

These results suggest DNMT3A mutations arise earlier than NPM1 and FLT3-ITD mutations, the researchers said.

To determine the origin of mutated DNMT3A, they analyzed hematopoietic stem and progenitor cell populations from 11 patients with DNMT3A and NPM1 mutations.

While both types of mutations were present in CD33+ blasts, mutant DNMT3A was present without mutant NPM1 across the spectrum of mature and progenitor cell populations.

Experiments in mice revealed that DNMT3A-mutant HSCs had a multilineage repopulation advantage over non-mutant HSCs. This, the investigators said, establishes the mutant cells as pre-leukemic HSCs.

The team also found the pre-leukemic HSCs in samples taken from AML patients in remission, which showed that the cells survived chemotherapy.

The researchers therefore concluded that DNMT3A mutations arise early in AML evolution and lead to a clonally expanded pool of pre-leukemic HSCs from which AML develops.

“By peering into the ‘black box’ of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding,” Dr Dick said. “People tend to think relapse after remission means chemotherapy didn’t kill all the cancer cells.”

“Our study suggests that, in some cases, the chemotherapy does, in fact, eradicate AML. What it does not touch are the pre-leukemic stem cells that can trigger another round of AML development and, ultimately, disease relapse.”

Dr Dick believes this finding could spawn accelerated drug development to specifically target DNMT3A. The discovery should also provide impetus for researchers to look for pre-cancerous cells in AML patients with other mutations.

A new study has shown that hematopoietic stem cells (HSCs) can acquire mutations in DNMT3A, and this may be the first step in initiating acute myeloid leukemia (AML).

These HSCs also appear to be a means of treatment resistance and may trigger relapse in patients with AML, investigators reported in Nature.

“Our discovery lays the groundwork to detect and target the pre-leukemic stem cell and thereby potentially stop the disease at a very early stage, when it may be more amenable to treatment,” said study author John Dick, PhD, of the University of Toronto in Ontario, Canada.

“Now, we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse.”

Dr Dick and his colleagues analyzed 71 samples from AML patients and discovered that 17 of them (24%) carried mutations in DNMT3A. Fifteen of those samples (88%) also had mutated NPM1.

Both mutations were present in patients’ blasts. But 12 patients (70.5%) had T cells that contained DNMT3A mutations but no NPM1 mutations. FLT3-ITD mutations were also present in blasts but not T cells in 2 patients.

These results suggest DNMT3A mutations arise earlier than NPM1 and FLT3-ITD mutations, the researchers said.

To determine the origin of mutated DNMT3A, they analyzed hematopoietic stem and progenitor cell populations from 11 patients with DNMT3A and NPM1 mutations.

While both types of mutations were present in CD33+ blasts, mutant DNMT3A was present without mutant NPM1 across the spectrum of mature and progenitor cell populations.

Experiments in mice revealed that DNMT3A-mutant HSCs had a multilineage repopulation advantage over non-mutant HSCs. This, the investigators said, establishes the mutant cells as pre-leukemic HSCs.

The team also found the pre-leukemic HSCs in samples taken from AML patients in remission, which showed that the cells survived chemotherapy.

The researchers therefore concluded that DNMT3A mutations arise early in AML evolution and lead to a clonally expanded pool of pre-leukemic HSCs from which AML develops.

“By peering into the ‘black box’ of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding,” Dr Dick said. “People tend to think relapse after remission means chemotherapy didn’t kill all the cancer cells.”

“Our study suggests that, in some cases, the chemotherapy does, in fact, eradicate AML. What it does not touch are the pre-leukemic stem cells that can trigger another round of AML development and, ultimately, disease relapse.”

Dr Dick believes this finding could spawn accelerated drug development to specifically target DNMT3A. The discovery should also provide impetus for researchers to look for pre-cancerous cells in AML patients with other mutations.

A new study has shown that hematopoietic stem cells (HSCs) can acquire mutations in DNMT3A, and this may be the first step in initiating acute myeloid leukemia (AML).

These HSCs also appear to be a means of treatment resistance and may trigger relapse in patients with AML, investigators reported in Nature.

“Our discovery lays the groundwork to detect and target the pre-leukemic stem cell and thereby potentially stop the disease at a very early stage, when it may be more amenable to treatment,” said study author John Dick, PhD, of the University of Toronto in Ontario, Canada.

“Now, we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse.”

Dr Dick and his colleagues analyzed 71 samples from AML patients and discovered that 17 of them (24%) carried mutations in DNMT3A. Fifteen of those samples (88%) also had mutated NPM1.

Both mutations were present in patients’ blasts. But 12 patients (70.5%) had T cells that contained DNMT3A mutations but no NPM1 mutations. FLT3-ITD mutations were also present in blasts but not T cells in 2 patients.

These results suggest DNMT3A mutations arise earlier than NPM1 and FLT3-ITD mutations, the researchers said.

To determine the origin of mutated DNMT3A, they analyzed hematopoietic stem and progenitor cell populations from 11 patients with DNMT3A and NPM1 mutations.

While both types of mutations were present in CD33+ blasts, mutant DNMT3A was present without mutant NPM1 across the spectrum of mature and progenitor cell populations.

Experiments in mice revealed that DNMT3A-mutant HSCs had a multilineage repopulation advantage over non-mutant HSCs. This, the investigators said, establishes the mutant cells as pre-leukemic HSCs.

The team also found the pre-leukemic HSCs in samples taken from AML patients in remission, which showed that the cells survived chemotherapy.

The researchers therefore concluded that DNMT3A mutations arise early in AML evolution and lead to a clonally expanded pool of pre-leukemic HSCs from which AML develops.

“By peering into the ‘black box’ of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding,” Dr Dick said. “People tend to think relapse after remission means chemotherapy didn’t kill all the cancer cells.”

“Our study suggests that, in some cases, the chemotherapy does, in fact, eradicate AML. What it does not touch are the pre-leukemic stem cells that can trigger another round of AML development and, ultimately, disease relapse.”

Dr Dick believes this finding could spawn accelerated drug development to specifically target DNMT3A. The discovery should also provide impetus for researchers to look for pre-cancerous cells in AML patients with other mutations.

Prescription medications

Credit: CDC

Health Canada has approved pomalidomide (Pomalyst) for use in combination with dexamethasone to treat patients with relapsed or refractory multiple myeloma (MM).

Patients must have received at least 2 prior therapies, failed treatment with lenalidomide and bortezomib, and experienced disease progression while on their last treatment regimen.

Health Canada had given pomalidomide priority review status due to the unmet need of effective therapies for patients with aggressive MM.

“Until now, there have been no approved options for patients whose disease has progressed despite available treatments,” said Donna E. Reece, MD, of the Princess Margaret Cancer Centre in Toronto.

“With Pomalyst, we have a new option that extends periods of remission, is generally well-tolerated, and can be taken in the convenience of a patient’s home.”

Trial prompts approval

Health Canada based its approval of pomalidomide on findings from the MM-003 trial. Regulatory agencies in the United States and European Union, both of which approved pomalidomide last year, based their decisions on the results of this study as well.

The phase 3 trial included 455 patients with relapsed or refractory MM who had received a median of 5 prior treatment regimens.

Patients were randomized to receive pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone alone (HiDEX, n=153). The median follow-up was 10 months.

Researchers found that response and survival rates were superior in the POM-LoDEX arm, and rates of adverse events were largely similar between the 2 arms.

The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months and 6.1 months, respectively.

The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).

Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar.

Rates of grade 3/4 non-hematologic toxicities were also comparable and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.

These results were presented at the 2013 ASCO Annual Meeting and published in The Lancet Oncology in October.

Drug availability

Pomalidomide is expected to be commercially available in Canada in March.

The drug will be distributed through a risk-management program called RevAid, which was developed in 2008. By adding pomalidomide to the program, regulators are aiming to prevent fetal exposure to the drug because of its structural similarities to thalidomide, a known human teratogen.

Under the program, only prescribers and pharmacists registered with RevAid are able to prescribe and dispense pomalidomide. In addition, only those patients who are registered and meet all the conditions of the RevAid program will receive the drug.

Prescription medications

Credit: CDC

Health Canada has approved pomalidomide (Pomalyst) for use in combination with dexamethasone to treat patients with relapsed or refractory multiple myeloma (MM).

Patients must have received at least 2 prior therapies, failed treatment with lenalidomide and bortezomib, and experienced disease progression while on their last treatment regimen.

Health Canada had given pomalidomide priority review status due to the unmet need of effective therapies for patients with aggressive MM.

“Until now, there have been no approved options for patients whose disease has progressed despite available treatments,” said Donna E. Reece, MD, of the Princess Margaret Cancer Centre in Toronto.

“With Pomalyst, we have a new option that extends periods of remission, is generally well-tolerated, and can be taken in the convenience of a patient’s home.”

Trial prompts approval

Health Canada based its approval of pomalidomide on findings from the MM-003 trial. Regulatory agencies in the United States and European Union, both of which approved pomalidomide last year, based their decisions on the results of this study as well.

The phase 3 trial included 455 patients with relapsed or refractory MM who had received a median of 5 prior treatment regimens.

Patients were randomized to receive pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone alone (HiDEX, n=153). The median follow-up was 10 months.

Researchers found that response and survival rates were superior in the POM-LoDEX arm, and rates of adverse events were largely similar between the 2 arms.

The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months and 6.1 months, respectively.

The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).

Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar.

Rates of grade 3/4 non-hematologic toxicities were also comparable and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.

These results were presented at the 2013 ASCO Annual Meeting and published in The Lancet Oncology in October.

Drug availability

Pomalidomide is expected to be commercially available in Canada in March.

The drug will be distributed through a risk-management program called RevAid, which was developed in 2008. By adding pomalidomide to the program, regulators are aiming to prevent fetal exposure to the drug because of its structural similarities to thalidomide, a known human teratogen.

Under the program, only prescribers and pharmacists registered with RevAid are able to prescribe and dispense pomalidomide. In addition, only those patients who are registered and meet all the conditions of the RevAid program will receive the drug.

Prescription medications

Credit: CDC

Health Canada has approved pomalidomide (Pomalyst) for use in combination with dexamethasone to treat patients with relapsed or refractory multiple myeloma (MM).

Patients must have received at least 2 prior therapies, failed treatment with lenalidomide and bortezomib, and experienced disease progression while on their last treatment regimen.

Health Canada had given pomalidomide priority review status due to the unmet need of effective therapies for patients with aggressive MM.

“Until now, there have been no approved options for patients whose disease has progressed despite available treatments,” said Donna E. Reece, MD, of the Princess Margaret Cancer Centre in Toronto.

“With Pomalyst, we have a new option that extends periods of remission, is generally well-tolerated, and can be taken in the convenience of a patient’s home.”

Trial prompts approval

Health Canada based its approval of pomalidomide on findings from the MM-003 trial. Regulatory agencies in the United States and European Union, both of which approved pomalidomide last year, based their decisions on the results of this study as well.

The phase 3 trial included 455 patients with relapsed or refractory MM who had received a median of 5 prior treatment regimens.

Patients were randomized to receive pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone alone (HiDEX, n=153). The median follow-up was 10 months.

Researchers found that response and survival rates were superior in the POM-LoDEX arm, and rates of adverse events were largely similar between the 2 arms.

The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months and 6.1 months, respectively.

The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).

Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar.

Rates of grade 3/4 non-hematologic toxicities were also comparable and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.

These results were presented at the 2013 ASCO Annual Meeting and published in The Lancet Oncology in October.

Drug availability

Pomalidomide is expected to be commercially available in Canada in March.

The drug will be distributed through a risk-management program called RevAid, which was developed in 2008. By adding pomalidomide to the program, regulators are aiming to prevent fetal exposure to the drug because of its structural similarities to thalidomide, a known human teratogen.

Under the program, only prescribers and pharmacists registered with RevAid are able to prescribe and dispense pomalidomide. In addition, only those patients who are registered and meet all the conditions of the RevAid program will receive the drug.

AML cells in the bone marrow

Results of preclinical research suggest the wild-type version of SYK pairs with mutated FLT3 to promote progression of acute myelogenous leukemia (AML).

And this molecular partnership promotes AML cells’ resistance to FLT3 inhibitors.

However, adding a SYK inhibitor to the mix can override this resistance. In an animal model of AML, treatment with a combination of FLT3 and SYK inhibitors was significantly more effective than either inhibitor alone.

These findings, published in Cancer Cell, raise hopes that treatment strategies focusing on both enzymes simultaneously could improve outcomes for patients with FLT3-ITD AML.

“Patients whose AML cells express FLT3-ITD are among the highest-risk group of patients with AML,” said study author Kimberly Stegmaier, MD, of the Dana-Farber Cancer Institute in Boston. “Their AML is particularly difficult to treat.”

In 2009, researchers in Dr Stegmaier’s lab discovered that SYK, a kinase that had attracted attention for its role in other malignancies, could be a potential drug target in AML. Unlike other cancer-associated kinases, SYK rarely undergoes mutations or other genomic alterations in cancer cells, remaining in its wild-type form.

With the current study, Dr Stegmaier and her colleagues set out to better understand SYK’s role in AML. The team screened AML cell lines to reveal the full scope of the enzyme’s molecular interactions. And they found evidence of strong interactions between wild-type SYK and mutated FLT3, particularly FLT3-ITD.

“We wanted to understand the cooperative oncologic effects by which SYK contributes to AML,” Dr Stegmaier said. “The concept of a normal enzyme aiding a mutant one has not yet been widely explored, and so we were both surprised and pleased to see FLT3-ITD come up as a high-priority hit in our screens.”

Through experiments in cell lines, primary patient samples, and animal models, the researchers found that SYK and FLT3-ITD’s interactions are a key ingredient in the progression of myeloproliferative neoplasms into AML. AML cells’ continued growth after turning malignant also relied on these interactions.

In addition, the team found that SYK’s hyperactivated form can promote resistance to the FLT3-targeting drug quizartinib. However, a combination of quizartinib and the SYK inhibitor PRT062607 overcame this resistance, significantly increasing survival and reducing signs of disease in a FLT3-ITD AML mouse model.

Highlighting their findings’ clinical relevance, the researchers found strong SYK activity in cells from FLT3-ITD AML patients. The cells were also highly sensitive to SYK inhibition.

“These data affirm that SYK is an important target in AML,” Dr Stegmaier said. “They also suggest that interactions between oncologic kinases and SYK or other wild-type enzymes may contribute to resistance of kinase inhibitors more broadly.”

Dr Stegmaier added that, over the course of this research, the team has developed a suite of tools that could prove useful for future clinical studies of treatments with SYK inhibitors or SYK inhibitors in combination with FLT3 inhibitors.

“We have not only identified SYK as a candidate treatment target in AML, but we have also identified a specific population of patients with AML more likely to respond to SYK inhibitors: patients with FLT3 mutations,” she said.

“Moreover, we have developed tools for identifying patients with high levels of SYK and FLT3 activation and can monitor these 2 targets while patients are receiving treatment. Predictive biomarkers of response are becoming increasingly important in the development of effective clinical trials of targeted therapies.”

AML cells in the bone marrow

Results of preclinical research suggest the wild-type version of SYK pairs with mutated FLT3 to promote progression of acute myelogenous leukemia (AML).

And this molecular partnership promotes AML cells’ resistance to FLT3 inhibitors.

However, adding a SYK inhibitor to the mix can override this resistance. In an animal model of AML, treatment with a combination of FLT3 and SYK inhibitors was significantly more effective than either inhibitor alone.

These findings, published in Cancer Cell, raise hopes that treatment strategies focusing on both enzymes simultaneously could improve outcomes for patients with FLT3-ITD AML.

“Patients whose AML cells express FLT3-ITD are among the highest-risk group of patients with AML,” said study author Kimberly Stegmaier, MD, of the Dana-Farber Cancer Institute in Boston. “Their AML is particularly difficult to treat.”

In 2009, researchers in Dr Stegmaier’s lab discovered that SYK, a kinase that had attracted attention for its role in other malignancies, could be a potential drug target in AML. Unlike other cancer-associated kinases, SYK rarely undergoes mutations or other genomic alterations in cancer cells, remaining in its wild-type form.

With the current study, Dr Stegmaier and her colleagues set out to better understand SYK’s role in AML. The team screened AML cell lines to reveal the full scope of the enzyme’s molecular interactions. And they found evidence of strong interactions between wild-type SYK and mutated FLT3, particularly FLT3-ITD.

“We wanted to understand the cooperative oncologic effects by which SYK contributes to AML,” Dr Stegmaier said. “The concept of a normal enzyme aiding a mutant one has not yet been widely explored, and so we were both surprised and pleased to see FLT3-ITD come up as a high-priority hit in our screens.”

Through experiments in cell lines, primary patient samples, and animal models, the researchers found that SYK and FLT3-ITD’s interactions are a key ingredient in the progression of myeloproliferative neoplasms into AML. AML cells’ continued growth after turning malignant also relied on these interactions.

In addition, the team found that SYK’s hyperactivated form can promote resistance to the FLT3-targeting drug quizartinib. However, a combination of quizartinib and the SYK inhibitor PRT062607 overcame this resistance, significantly increasing survival and reducing signs of disease in a FLT3-ITD AML mouse model.

Highlighting their findings’ clinical relevance, the researchers found strong SYK activity in cells from FLT3-ITD AML patients. The cells were also highly sensitive to SYK inhibition.

“These data affirm that SYK is an important target in AML,” Dr Stegmaier said. “They also suggest that interactions between oncologic kinases and SYK or other wild-type enzymes may contribute to resistance of kinase inhibitors more broadly.”

Dr Stegmaier added that, over the course of this research, the team has developed a suite of tools that could prove useful for future clinical studies of treatments with SYK inhibitors or SYK inhibitors in combination with FLT3 inhibitors.

“We have not only identified SYK as a candidate treatment target in AML, but we have also identified a specific population of patients with AML more likely to respond to SYK inhibitors: patients with FLT3 mutations,” she said.

“Moreover, we have developed tools for identifying patients with high levels of SYK and FLT3 activation and can monitor these 2 targets while patients are receiving treatment. Predictive biomarkers of response are becoming increasingly important in the development of effective clinical trials of targeted therapies.”

AML cells in the bone marrow

Results of preclinical research suggest the wild-type version of SYK pairs with mutated FLT3 to promote progression of acute myelogenous leukemia (AML).

And this molecular partnership promotes AML cells’ resistance to FLT3 inhibitors.

However, adding a SYK inhibitor to the mix can override this resistance. In an animal model of AML, treatment with a combination of FLT3 and SYK inhibitors was significantly more effective than either inhibitor alone.

These findings, published in Cancer Cell, raise hopes that treatment strategies focusing on both enzymes simultaneously could improve outcomes for patients with FLT3-ITD AML.

“Patients whose AML cells express FLT3-ITD are among the highest-risk group of patients with AML,” said study author Kimberly Stegmaier, MD, of the Dana-Farber Cancer Institute in Boston. “Their AML is particularly difficult to treat.”

In 2009, researchers in Dr Stegmaier’s lab discovered that SYK, a kinase that had attracted attention for its role in other malignancies, could be a potential drug target in AML. Unlike other cancer-associated kinases, SYK rarely undergoes mutations or other genomic alterations in cancer cells, remaining in its wild-type form.

With the current study, Dr Stegmaier and her colleagues set out to better understand SYK’s role in AML. The team screened AML cell lines to reveal the full scope of the enzyme’s molecular interactions. And they found evidence of strong interactions between wild-type SYK and mutated FLT3, particularly FLT3-ITD.

“We wanted to understand the cooperative oncologic effects by which SYK contributes to AML,” Dr Stegmaier said. “The concept of a normal enzyme aiding a mutant one has not yet been widely explored, and so we were both surprised and pleased to see FLT3-ITD come up as a high-priority hit in our screens.”

Through experiments in cell lines, primary patient samples, and animal models, the researchers found that SYK and FLT3-ITD’s interactions are a key ingredient in the progression of myeloproliferative neoplasms into AML. AML cells’ continued growth after turning malignant also relied on these interactions.

In addition, the team found that SYK’s hyperactivated form can promote resistance to the FLT3-targeting drug quizartinib. However, a combination of quizartinib and the SYK inhibitor PRT062607 overcame this resistance, significantly increasing survival and reducing signs of disease in a FLT3-ITD AML mouse model.

Highlighting their findings’ clinical relevance, the researchers found strong SYK activity in cells from FLT3-ITD AML patients. The cells were also highly sensitive to SYK inhibition.

“These data affirm that SYK is an important target in AML,” Dr Stegmaier said. “They also suggest that interactions between oncologic kinases and SYK or other wild-type enzymes may contribute to resistance of kinase inhibitors more broadly.”

Dr Stegmaier added that, over the course of this research, the team has developed a suite of tools that could prove useful for future clinical studies of treatments with SYK inhibitors or SYK inhibitors in combination with FLT3 inhibitors.

“We have not only identified SYK as a candidate treatment target in AML, but we have also identified a specific population of patients with AML more likely to respond to SYK inhibitors: patients with FLT3 mutations,” she said.

“Moreover, we have developed tools for identifying patients with high levels of SYK and FLT3 activation and can monitor these 2 targets while patients are receiving treatment. Predictive biomarkers of response are becoming increasingly important in the development of effective clinical trials of targeted therapies.”

Cell culture in a petri dish

Researchers say they’ve identified 20 proteins specific to primary effusion lymphoma (PEL).

The proteins, which were found by growing PEL cells in culture and analyzing the secretome, may explain PEL pathogenesis, its peculiar cell adhesion, and migration patterns.

The investigators also uncovered related oncogenic pathways, which could pave the way for more individualized treatment of PEL.

These findings appear in The American Journal of Pathology.

The researchers analyzed secretomes from 4 established PEL cell lines—CRO-AP2, CRO-AP3, CRO-AP5, and CRO-AP6—as well as from 4 PEL clinical samples and 3 primary solid lymphomas. PEL cells are characterized by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, and the primary solid lymphomas were KSHV-positive as well.

The investigators measured protein content using 2 complementary mass spectrometry platforms. The experiments allowed cells to grow for 16 to 18 hours and were performed under serum-free conditions to increase the ability to detect secreted proteins.

Of the 266 proteins identified, 139 (52%) were secreted, and 127 were considered to have an intracellular origin or were secreted in an unconventional fashion.

“Most of the proteins we recognized in the secretome of PEL are new with respect to previous studies utilizing conventional proteomic analysis and gene expression profiling,” said study author Annunziata Gloghini, PhD, of Istituto Nazionale dei Tumori in Milan, Italy.

“Importantly, 27 proteins were shared by secretomes from all PEL cell lines.”

The PEL secretomes were enriched with proteins specifically involved in inflammation and the immune response—such as HMGB1, GRAA, and PCBP2—as well as cell growth—such as LEG1, STMN1, and S10A6.

Other proteins are known to play roles in mRNA processing—such as ANM1 and PCBP2—or cell structure, adhesion, migration, and organization—such as EZRI and MOES. Some of the proteins have enzymatic activity—such as CATA and GSTK1.

A comparison of secretomes from PEL with those from other tumor cell lines revealed 20 proteins specific to the PEL cell lines. This suggests secretome profiling provides a source of tumor biomarkers and may ultimately improve patient management, the researchers said.

The group also conducted pathway/network enrichment analyses and found that the pathways most activated in PEL cell lines were involved with the regulation of autophagy through LRRK2-mediated signaling pathways and with apoptosis and survival through granzyme A signaling.

“The extracellular functions of granzyme A might be involved in the particular tropism of PEL and its cell growth,” said study author Italia Bongarzone, PhD, also of the Istituto Nazionale dei Tumori.

“Further studies are needed to confirm and validate the importance of these pathways/processes and their roles in lymphoma tumorigenesis and progression.”

Cell culture in a petri dish

Researchers say they’ve identified 20 proteins specific to primary effusion lymphoma (PEL).

The proteins, which were found by growing PEL cells in culture and analyzing the secretome, may explain PEL pathogenesis, its peculiar cell adhesion, and migration patterns.

The investigators also uncovered related oncogenic pathways, which could pave the way for more individualized treatment of PEL.

These findings appear in The American Journal of Pathology.

The researchers analyzed secretomes from 4 established PEL cell lines—CRO-AP2, CRO-AP3, CRO-AP5, and CRO-AP6—as well as from 4 PEL clinical samples and 3 primary solid lymphomas. PEL cells are characterized by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, and the primary solid lymphomas were KSHV-positive as well.

The investigators measured protein content using 2 complementary mass spectrometry platforms. The experiments allowed cells to grow for 16 to 18 hours and were performed under serum-free conditions to increase the ability to detect secreted proteins.

Of the 266 proteins identified, 139 (52%) were secreted, and 127 were considered to have an intracellular origin or were secreted in an unconventional fashion.

“Most of the proteins we recognized in the secretome of PEL are new with respect to previous studies utilizing conventional proteomic analysis and gene expression profiling,” said study author Annunziata Gloghini, PhD, of Istituto Nazionale dei Tumori in Milan, Italy.

“Importantly, 27 proteins were shared by secretomes from all PEL cell lines.”

The PEL secretomes were enriched with proteins specifically involved in inflammation and the immune response—such as HMGB1, GRAA, and PCBP2—as well as cell growth—such as LEG1, STMN1, and S10A6.

Other proteins are known to play roles in mRNA processing—such as ANM1 and PCBP2—or cell structure, adhesion, migration, and organization—such as EZRI and MOES. Some of the proteins have enzymatic activity—such as CATA and GSTK1.

A comparison of secretomes from PEL with those from other tumor cell lines revealed 20 proteins specific to the PEL cell lines. This suggests secretome profiling provides a source of tumor biomarkers and may ultimately improve patient management, the researchers said.

The group also conducted pathway/network enrichment analyses and found that the pathways most activated in PEL cell lines were involved with the regulation of autophagy through LRRK2-mediated signaling pathways and with apoptosis and survival through granzyme A signaling.

“The extracellular functions of granzyme A might be involved in the particular tropism of PEL and its cell growth,” said study author Italia Bongarzone, PhD, also of the Istituto Nazionale dei Tumori.

“Further studies are needed to confirm and validate the importance of these pathways/processes and their roles in lymphoma tumorigenesis and progression.”

Cell culture in a petri dish

Researchers say they’ve identified 20 proteins specific to primary effusion lymphoma (PEL).

The proteins, which were found by growing PEL cells in culture and analyzing the secretome, may explain PEL pathogenesis, its peculiar cell adhesion, and migration patterns.

The investigators also uncovered related oncogenic pathways, which could pave the way for more individualized treatment of PEL.

These findings appear in The American Journal of Pathology.

The researchers analyzed secretomes from 4 established PEL cell lines—CRO-AP2, CRO-AP3, CRO-AP5, and CRO-AP6—as well as from 4 PEL clinical samples and 3 primary solid lymphomas. PEL cells are characterized by Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, and the primary solid lymphomas were KSHV-positive as well.

The investigators measured protein content using 2 complementary mass spectrometry platforms. The experiments allowed cells to grow for 16 to 18 hours and were performed under serum-free conditions to increase the ability to detect secreted proteins.

Of the 266 proteins identified, 139 (52%) were secreted, and 127 were considered to have an intracellular origin or were secreted in an unconventional fashion.

“Most of the proteins we recognized in the secretome of PEL are new with respect to previous studies utilizing conventional proteomic analysis and gene expression profiling,” said study author Annunziata Gloghini, PhD, of Istituto Nazionale dei Tumori in Milan, Italy.

“Importantly, 27 proteins were shared by secretomes from all PEL cell lines.”

The PEL secretomes were enriched with proteins specifically involved in inflammation and the immune response—such as HMGB1, GRAA, and PCBP2—as well as cell growth—such as LEG1, STMN1, and S10A6.

Other proteins are known to play roles in mRNA processing—such as ANM1 and PCBP2—or cell structure, adhesion, migration, and organization—such as EZRI and MOES. Some of the proteins have enzymatic activity—such as CATA and GSTK1.

A comparison of secretomes from PEL with those from other tumor cell lines revealed 20 proteins specific to the PEL cell lines. This suggests secretome profiling provides a source of tumor biomarkers and may ultimately improve patient management, the researchers said.

The group also conducted pathway/network enrichment analyses and found that the pathways most activated in PEL cell lines were involved with the regulation of autophagy through LRRK2-mediated signaling pathways and with apoptosis and survival through granzyme A signaling.

“The extracellular functions of granzyme A might be involved in the particular tropism of PEL and its cell growth,” said study author Italia Bongarzone, PhD, also of the Istituto Nazionale dei Tumori.

“Further studies are needed to confirm and validate the importance of these pathways/processes and their roles in lymphoma tumorigenesis and progression.”

Cells printed via BloC-Printing

Credit: Lidong Qin lab

A new technique allows scientists to print living cells onto any surface in virtually any shape, according to a paper published in Proceedings of the National Academy of Sciences.

The approach, called Block-Cell-Printing (BloC-Printing), produces 2-D cell arrays in as little as half an hour, prints the cells as close together as 5 μm, and allows for the use of different cell types.

And unlike similar work using inkjet printing approaches, almost all cells survive BloC-Printing.

“Cell printing is used in so many different ways now—for drug development and in studies of tissue regeneration, cell function, and cell-cell communication,” said study author Lidong Qin, PhD, of Houston Methodist Research Institute in Texas.

“Such things can only be done when cells are alive and active. A survival rate of 50% to 80% is typical as cells exit the inkjet nozzles. By comparison, we are seeing close to 100% of cells in BloC-Printing survive the printing process.”

On the other hand, Dr Qin noted that inkjet printing remains faster than BloC-Printing. And BloC-Printing cannot yet print multi-layer structures as inkjetting can.

BloC-Printing manipulates microfluidic physics to guide living cells into hook-like traps in a silicone mold. Cells flow down a column in the mold, past trapped cells to the next available slot, eventually creating a line of cells (in a grid of such lines).

The position and spacing of the traps and the shape of the channel navigated by the cells is fully configurable during the mold’s creation. When the mold is lifted away, the living cells remain behind, adhering to the growth medium or other substrate in prescribed formation.

Dr Qin’s group tested BloC-Printing for its utility in studying breast cancer cells and primary neurons.

By arranging the cancer cells in a grid and examining their growth in comparison with a non-metastatic control, the researchers found they could easily characterize the metastatic potential of the cancer cells.

“We looked at cancer cells for their protrusion generation capability, which correlates to their malignancy level,” Dr Qin said. “Longer protrusion means more aggressive cancer cells. The measurement may help to diagnose a cancer’s stage.”

The researchers also printed a grid of brain cells and gave the cells time to form synaptic and autaptic junctions.

“The cell junctions we created may be useful for future neuron signal transduction and axon regeneration studies,” Dr Qin said. “Such work could be helpful in understanding Alzheimer’s disease and other neurodegenerative diseases.”

While it is too early to predict the market cost of BloC-Printing, Dr Qin said the materials of a single BloC mold cost about $1. After the mold has been fabricated and delivered, a researcher only needs a syringe, a carefully prepared suspension of living cells, a Petri dish, and a steady hand.

“BloC-Printing can be combined with molecular printing for many types of drug screening, RNA interference, and molecule-cell interaction studies,” Dr Qin said. “We believe the technology has big potential.”

Cells printed via BloC-Printing

Credit: Lidong Qin lab

A new technique allows scientists to print living cells onto any surface in virtually any shape, according to a paper published in Proceedings of the National Academy of Sciences.

The approach, called Block-Cell-Printing (BloC-Printing), produces 2-D cell arrays in as little as half an hour, prints the cells as close together as 5 μm, and allows for the use of different cell types.

And unlike similar work using inkjet printing approaches, almost all cells survive BloC-Printing.

“Cell printing is used in so many different ways now—for drug development and in studies of tissue regeneration, cell function, and cell-cell communication,” said study author Lidong Qin, PhD, of Houston Methodist Research Institute in Texas.

“Such things can only be done when cells are alive and active. A survival rate of 50% to 80% is typical as cells exit the inkjet nozzles. By comparison, we are seeing close to 100% of cells in BloC-Printing survive the printing process.”

On the other hand, Dr Qin noted that inkjet printing remains faster than BloC-Printing. And BloC-Printing cannot yet print multi-layer structures as inkjetting can.

BloC-Printing manipulates microfluidic physics to guide living cells into hook-like traps in a silicone mold. Cells flow down a column in the mold, past trapped cells to the next available slot, eventually creating a line of cells (in a grid of such lines).

The position and spacing of the traps and the shape of the channel navigated by the cells is fully configurable during the mold’s creation. When the mold is lifted away, the living cells remain behind, adhering to the growth medium or other substrate in prescribed formation.

Dr Qin’s group tested BloC-Printing for its utility in studying breast cancer cells and primary neurons.

By arranging the cancer cells in a grid and examining their growth in comparison with a non-metastatic control, the researchers found they could easily characterize the metastatic potential of the cancer cells.

“We looked at cancer cells for their protrusion generation capability, which correlates to their malignancy level,” Dr Qin said. “Longer protrusion means more aggressive cancer cells. The measurement may help to diagnose a cancer’s stage.”

The researchers also printed a grid of brain cells and gave the cells time to form synaptic and autaptic junctions.

“The cell junctions we created may be useful for future neuron signal transduction and axon regeneration studies,” Dr Qin said. “Such work could be helpful in understanding Alzheimer’s disease and other neurodegenerative diseases.”

While it is too early to predict the market cost of BloC-Printing, Dr Qin said the materials of a single BloC mold cost about $1. After the mold has been fabricated and delivered, a researcher only needs a syringe, a carefully prepared suspension of living cells, a Petri dish, and a steady hand.

“BloC-Printing can be combined with molecular printing for many types of drug screening, RNA interference, and molecule-cell interaction studies,” Dr Qin said. “We believe the technology has big potential.”

Cells printed via BloC-Printing

Credit: Lidong Qin lab

A new technique allows scientists to print living cells onto any surface in virtually any shape, according to a paper published in Proceedings of the National Academy of Sciences.

The approach, called Block-Cell-Printing (BloC-Printing), produces 2-D cell arrays in as little as half an hour, prints the cells as close together as 5 μm, and allows for the use of different cell types.

And unlike similar work using inkjet printing approaches, almost all cells survive BloC-Printing.

“Cell printing is used in so many different ways now—for drug development and in studies of tissue regeneration, cell function, and cell-cell communication,” said study author Lidong Qin, PhD, of Houston Methodist Research Institute in Texas.

“Such things can only be done when cells are alive and active. A survival rate of 50% to 80% is typical as cells exit the inkjet nozzles. By comparison, we are seeing close to 100% of cells in BloC-Printing survive the printing process.”

On the other hand, Dr Qin noted that inkjet printing remains faster than BloC-Printing. And BloC-Printing cannot yet print multi-layer structures as inkjetting can.

BloC-Printing manipulates microfluidic physics to guide living cells into hook-like traps in a silicone mold. Cells flow down a column in the mold, past trapped cells to the next available slot, eventually creating a line of cells (in a grid of such lines).

The position and spacing of the traps and the shape of the channel navigated by the cells is fully configurable during the mold’s creation. When the mold is lifted away, the living cells remain behind, adhering to the growth medium or other substrate in prescribed formation.

Dr Qin’s group tested BloC-Printing for its utility in studying breast cancer cells and primary neurons.

By arranging the cancer cells in a grid and examining their growth in comparison with a non-metastatic control, the researchers found they could easily characterize the metastatic potential of the cancer cells.

“We looked at cancer cells for their protrusion generation capability, which correlates to their malignancy level,” Dr Qin said. “Longer protrusion means more aggressive cancer cells. The measurement may help to diagnose a cancer’s stage.”

The researchers also printed a grid of brain cells and gave the cells time to form synaptic and autaptic junctions.

“The cell junctions we created may be useful for future neuron signal transduction and axon regeneration studies,” Dr Qin said. “Such work could be helpful in understanding Alzheimer’s disease and other neurodegenerative diseases.”

While it is too early to predict the market cost of BloC-Printing, Dr Qin said the materials of a single BloC mold cost about $1. After the mold has been fabricated and delivered, a researcher only needs a syringe, a carefully prepared suspension of living cells, a Petri dish, and a steady hand.

“BloC-Printing can be combined with molecular printing for many types of drug screening, RNA interference, and molecule-cell interaction studies,” Dr Qin said. “We believe the technology has big potential.”