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Tumor suppressor promotes FLT3-ITD AML
New research indicates that RUNX1, a known tumor suppressor, actually cooperates with internal tandem duplications in the FLT3 receptor tyrosine kinase (FLT3-ITD) to induce acute myeloid leukemia (AML).
Investigators say this discovery suggests that blocking RUNX1 activity will “greatly enhance” current therapeutic approaches using FLT3 inhibitors.
The discovery was published in The Journal of Experimental Medicine.
The research began when investigators noticed that many AML patients with FLT3-ITD also showed increased levels of RUNX1.
“This was unexpected because up to 20% of AML patients carry mutations that inactivate RUNX1, which is generally considered to be a tumor suppressor that prevents the formation of leukemias,” said study author Carol Stocking, PhD, of Heinrich-Pette-Institute-Leibniz Institute for Experimental Virology in Hamburg, Germany.
To investigate this finding, she and her colleagues injected mice with human AML cells expressing FLT3-ITD. The team found that reducing RUNX1 levels attenuated the cells’ ability to form tumors, but elevated RUNX1 levels worked with FLT3-ITD to induce AML.
Mouse hematopoietic stem cells expressing FLT3-ITD were highly proliferative, and co-expression of RUNX1 blocked their differentiation, allowing them to give rise to AML.
Mutant FLT3 appears to stabilize and activate RUNX1 by promoting the transcription factor’s phosphorylation. Active RUNX1 then blocks differentiation, at least in part, by upregulation of another transcription factor, Hhex.
The investigators found that hematopoietic stem cells expressing both Hhex and FLT3-ITD gave rise to AML.
RUNX1 may therefore suppress the initiation of AML but, after being activated by mutant FLT3, block differentiation and promote tumor development.
“Therapies that can reverse this differentiation block may offer significant therapeutic efficacy in AML patients with FLT3 mutations,” Dr Stocking said. “Ablating RUNX1 is toxic to leukemic cells but not to normal hematopoietic stem cells, so inhibiting RUNX1 may be a promising target in combination with FLT3 inhibitors.” 
New research indicates that RUNX1, a known tumor suppressor, actually cooperates with internal tandem duplications in the FLT3 receptor tyrosine kinase (FLT3-ITD) to induce acute myeloid leukemia (AML).
Investigators say this discovery suggests that blocking RUNX1 activity will “greatly enhance” current therapeutic approaches using FLT3 inhibitors.
The discovery was published in The Journal of Experimental Medicine.
The research began when investigators noticed that many AML patients with FLT3-ITD also showed increased levels of RUNX1.
“This was unexpected because up to 20% of AML patients carry mutations that inactivate RUNX1, which is generally considered to be a tumor suppressor that prevents the formation of leukemias,” said study author Carol Stocking, PhD, of Heinrich-Pette-Institute-Leibniz Institute for Experimental Virology in Hamburg, Germany.
To investigate this finding, she and her colleagues injected mice with human AML cells expressing FLT3-ITD. The team found that reducing RUNX1 levels attenuated the cells’ ability to form tumors, but elevated RUNX1 levels worked with FLT3-ITD to induce AML.
Mouse hematopoietic stem cells expressing FLT3-ITD were highly proliferative, and co-expression of RUNX1 blocked their differentiation, allowing them to give rise to AML.
Mutant FLT3 appears to stabilize and activate RUNX1 by promoting the transcription factor’s phosphorylation. Active RUNX1 then blocks differentiation, at least in part, by upregulation of another transcription factor, Hhex.
The investigators found that hematopoietic stem cells expressing both Hhex and FLT3-ITD gave rise to AML.
RUNX1 may therefore suppress the initiation of AML but, after being activated by mutant FLT3, block differentiation and promote tumor development.
“Therapies that can reverse this differentiation block may offer significant therapeutic efficacy in AML patients with FLT3 mutations,” Dr Stocking said. “Ablating RUNX1 is toxic to leukemic cells but not to normal hematopoietic stem cells, so inhibiting RUNX1 may be a promising target in combination with FLT3 inhibitors.”
New research indicates that RUNX1, a known tumor suppressor, actually cooperates with internal tandem duplications in the FLT3 receptor tyrosine kinase (FLT3-ITD) to induce acute myeloid leukemia (AML).
Investigators say this discovery suggests that blocking RUNX1 activity will “greatly enhance” current therapeutic approaches using FLT3 inhibitors.
The discovery was published in The Journal of Experimental Medicine.
The research began when investigators noticed that many AML patients with FLT3-ITD also showed increased levels of RUNX1.
“This was unexpected because up to 20% of AML patients carry mutations that inactivate RUNX1, which is generally considered to be a tumor suppressor that prevents the formation of leukemias,” said study author Carol Stocking, PhD, of Heinrich-Pette-Institute-Leibniz Institute for Experimental Virology in Hamburg, Germany.
To investigate this finding, she and her colleagues injected mice with human AML cells expressing FLT3-ITD. The team found that reducing RUNX1 levels attenuated the cells’ ability to form tumors, but elevated RUNX1 levels worked with FLT3-ITD to induce AML.
Mouse hematopoietic stem cells expressing FLT3-ITD were highly proliferative, and co-expression of RUNX1 blocked their differentiation, allowing them to give rise to AML.
Mutant FLT3 appears to stabilize and activate RUNX1 by promoting the transcription factor’s phosphorylation. Active RUNX1 then blocks differentiation, at least in part, by upregulation of another transcription factor, Hhex.
The investigators found that hematopoietic stem cells expressing both Hhex and FLT3-ITD gave rise to AML.
RUNX1 may therefore suppress the initiation of AML but, after being activated by mutant FLT3, block differentiation and promote tumor development.
“Therapies that can reverse this differentiation block may offer significant therapeutic efficacy in AML patients with FLT3 mutations,” Dr Stocking said. “Ablating RUNX1 is toxic to leukemic cells but not to normal hematopoietic stem cells, so inhibiting RUNX1 may be a promising target in combination with FLT3 inhibitors.”
Model illustrates progression to MDS, AML
Researchers say they have created a model that shows the step-by-step progression from normal blood cells to acute myeloid leukemia (AML).
The team generated induced pluripotent stem cell (iPSC) lines capturing disease stages that included preleukemia, low-risk myelodysplastic syndrome (MDS), high-risk MDS, and AML.
The researchers then used CRISPR/Cas9 genome editing to induce disease progression and reversal.
And they used the iPSCs to uncover disease-stage-specific effects of 2 drugs.
Eirini P. Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and her colleagues described this work in Cell Stem Cell.
The researchers first explained how they generated patient-derived iPSCs that represented familial predisposition to myeloid malignancy, low-risk and high-risk MDS, and AML.
By studying these iPSC lines, the team uncovered “a phenotypic road map of disease progression” that led to a “serially transplantable leukemia.”
“We are encouraged by the discovery that it was possible to generate potent, engraftable leukemia derived from AML induced pluripotent stem cells,” said study author Michael G. Kharas, PhD, of the Icahn School of Medicine at Mount Sinai.
The researchers also showed that they could revert a high-risk MDS iPSC line to a premalignant state by correcting a chromosome 7q deletion.
And they could force progression in a preleukemic iPSC line. The team induced progression to low-risk MDS by inactivating the second GATA2 allele and progression to high-risk MDS by deleting chromosome 7q.
“This work shows that integrated patient cell reprogramming and cancer genetics is a powerful way to dissect cancer progression,” Dr Kharas said.
The researchers reported that, ultimately, they were able to model the stepwise progression of normal cells to preleukemia and MDS by sequentially introducing genetic lesions associated with earlier and later disease stages (ASXL1 truncation and chromosome 7q deletion, respectively).
“The new model will empower investigation into the cellular and molecular events underlying the development of leukemia in ways that were not possible before,” Dr Papapetrou said.
She added that the group’s findings provide a framework to aid investigation into disease mechanisms, events driving progression, and drug responses.
In fact, the researchers did use hematopoietic progenitor cells (HPCs) derived from their iPSCs to analyze the disease-stage-specific effects of 2 drugs—5-azacytidine and rigosertib.
The team said they found evidence to suggest that 5-azacytidine may work in low-risk MDS by affecting differentiation, and the drug’s main therapeutic action in high-risk MDS might be mediated through selective inhibition of the MDS clone.
The researchers tested rigosertib in HPCs derived from 2 AML lines (from the same patient) that captured 2 different disease stages. One line was derived from the dominant clone (del 7q), and the other was derived from a KRAS-mutated subclone.
The team found that HPCs derived from the KRAS-mutated line demonstrated “marked sensitivity” to rigosertib, but the other HPCs were “marginally affected.”
Researchers say they have created a model that shows the step-by-step progression from normal blood cells to acute myeloid leukemia (AML).
The team generated induced pluripotent stem cell (iPSC) lines capturing disease stages that included preleukemia, low-risk myelodysplastic syndrome (MDS), high-risk MDS, and AML.
The researchers then used CRISPR/Cas9 genome editing to induce disease progression and reversal.
And they used the iPSCs to uncover disease-stage-specific effects of 2 drugs.
Eirini P. Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and her colleagues described this work in Cell Stem Cell.
The researchers first explained how they generated patient-derived iPSCs that represented familial predisposition to myeloid malignancy, low-risk and high-risk MDS, and AML.
By studying these iPSC lines, the team uncovered “a phenotypic road map of disease progression” that led to a “serially transplantable leukemia.”
“We are encouraged by the discovery that it was possible to generate potent, engraftable leukemia derived from AML induced pluripotent stem cells,” said study author Michael G. Kharas, PhD, of the Icahn School of Medicine at Mount Sinai.
The researchers also showed that they could revert a high-risk MDS iPSC line to a premalignant state by correcting a chromosome 7q deletion.
And they could force progression in a preleukemic iPSC line. The team induced progression to low-risk MDS by inactivating the second GATA2 allele and progression to high-risk MDS by deleting chromosome 7q.
“This work shows that integrated patient cell reprogramming and cancer genetics is a powerful way to dissect cancer progression,” Dr Kharas said.
The researchers reported that, ultimately, they were able to model the stepwise progression of normal cells to preleukemia and MDS by sequentially introducing genetic lesions associated with earlier and later disease stages (ASXL1 truncation and chromosome 7q deletion, respectively).
“The new model will empower investigation into the cellular and molecular events underlying the development of leukemia in ways that were not possible before,” Dr Papapetrou said.
She added that the group’s findings provide a framework to aid investigation into disease mechanisms, events driving progression, and drug responses.
In fact, the researchers did use hematopoietic progenitor cells (HPCs) derived from their iPSCs to analyze the disease-stage-specific effects of 2 drugs—5-azacytidine and rigosertib.
The team said they found evidence to suggest that 5-azacytidine may work in low-risk MDS by affecting differentiation, and the drug’s main therapeutic action in high-risk MDS might be mediated through selective inhibition of the MDS clone.
The researchers tested rigosertib in HPCs derived from 2 AML lines (from the same patient) that captured 2 different disease stages. One line was derived from the dominant clone (del 7q), and the other was derived from a KRAS-mutated subclone.
The team found that HPCs derived from the KRAS-mutated line demonstrated “marked sensitivity” to rigosertib, but the other HPCs were “marginally affected.”
Researchers say they have created a model that shows the step-by-step progression from normal blood cells to acute myeloid leukemia (AML).
The team generated induced pluripotent stem cell (iPSC) lines capturing disease stages that included preleukemia, low-risk myelodysplastic syndrome (MDS), high-risk MDS, and AML.
The researchers then used CRISPR/Cas9 genome editing to induce disease progression and reversal.
And they used the iPSCs to uncover disease-stage-specific effects of 2 drugs.
Eirini P. Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and her colleagues described this work in Cell Stem Cell.
The researchers first explained how they generated patient-derived iPSCs that represented familial predisposition to myeloid malignancy, low-risk and high-risk MDS, and AML.
By studying these iPSC lines, the team uncovered “a phenotypic road map of disease progression” that led to a “serially transplantable leukemia.”
“We are encouraged by the discovery that it was possible to generate potent, engraftable leukemia derived from AML induced pluripotent stem cells,” said study author Michael G. Kharas, PhD, of the Icahn School of Medicine at Mount Sinai.
The researchers also showed that they could revert a high-risk MDS iPSC line to a premalignant state by correcting a chromosome 7q deletion.
And they could force progression in a preleukemic iPSC line. The team induced progression to low-risk MDS by inactivating the second GATA2 allele and progression to high-risk MDS by deleting chromosome 7q.
“This work shows that integrated patient cell reprogramming and cancer genetics is a powerful way to dissect cancer progression,” Dr Kharas said.
The researchers reported that, ultimately, they were able to model the stepwise progression of normal cells to preleukemia and MDS by sequentially introducing genetic lesions associated with earlier and later disease stages (ASXL1 truncation and chromosome 7q deletion, respectively).
“The new model will empower investigation into the cellular and molecular events underlying the development of leukemia in ways that were not possible before,” Dr Papapetrou said.
She added that the group’s findings provide a framework to aid investigation into disease mechanisms, events driving progression, and drug responses.
In fact, the researchers did use hematopoietic progenitor cells (HPCs) derived from their iPSCs to analyze the disease-stage-specific effects of 2 drugs—5-azacytidine and rigosertib.
The team said they found evidence to suggest that 5-azacytidine may work in low-risk MDS by affecting differentiation, and the drug’s main therapeutic action in high-risk MDS might be mediated through selective inhibition of the MDS clone.
The researchers tested rigosertib in HPCs derived from 2 AML lines (from the same patient) that captured 2 different disease stages. One line was derived from the dominant clone (del 7q), and the other was derived from a KRAS-mutated subclone.
The team found that HPCs derived from the KRAS-mutated line demonstrated “marked sensitivity” to rigosertib, but the other HPCs were “marginally affected.”
Ublituximab was safe, highly active in rituximab-pretreated B-cell NHL, CLL
The investigational anti-CD20 monoclonal antibody ublituximab is safe and has good antitumor activity in patients with B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL) who have previously received the anti-CD20 antibody rituximab, results from a phase I/II trial suggest.
Ublituximab is engineered to have a low fucose content. This feature gives it enhanced antibody-dependent cellular cytotoxicity relative to other anti-CD20 antibodies, especially against tumors having low expression of that protein, as may occur in the development of rituximab resistance.
In the trial, nearly half of the 35 patients studied had a complete or partial response to ublituximab, including nearly one-third of those whose disease was refractory to rituximab (Rituxan) (Br J Haematol. 2017 Apr;177[2]:243-53). The main adverse events were infusion-related reactions, fatigue, pyrexia, and diarrhea, but almost all were lower grade.
“Ublituximab was well tolerated and efficacious in a heterogeneous and highly rituximab–pretreated patient population,” said the investigators, who were led by Ahmed Sawas, MD, at the Center for Lymphoid Malignancies, Columbia University Medical Center, N.Y.
The observed response rate is much the same as those seen with two other anti-CD20 antibodies – obinutuzumab (Gazyva)and ofatumumab (Arzerra)– in similar patient populations, and ublituximab may have advantages in terms of fewer higher-grade infusion-related reactions and shorter infusion time.
“Enhanced anti-CD20 [monoclonal antibodies] that are well tolerated and active in rituximab-resistant disease can provide meaningful clinical benefit to patients with limited treatment options,” the investigators noted.
The trial enrolled 27 patients with B-NHL and 8 patients with CLL (or small lymphocytic lymphoma) who had rituximab-refractory disease (defined by progression on or within 6 months of receiving that agent) or rituximab-relapsed disease (defined by progression more than 6 months after receiving it). They had received a median of three prior therapies.
The patients were treated on an open-label basis with ublituximab at various doses as induction therapy (3-4 weekly infusions during cycles 1 and 2) and then as maintenance therapy (monthly during cycles 3-5, then once every 3 months for up to 2 years). All patients received an oral antihistamine and steroids before infusions.
By the end of the trial, 60% of patients had discontinued treatment because of progression; 23% had discontinued because of adverse events, physician decision, or other reasons; and the remaining 17% had received all planned treatment, Dr. Sawas and his coinvestigators reported.
None of the patients experienced dose-limiting toxicities or unexpected adverse events. The rate of any-grade adverse events was 100%, and the rate specifically of grade 3/4 adverse events was 49%. The rate of serious adverse events (most commonly pneumonia) was 37%.
The leading nonhematologic adverse events were infusion-related reactions (40%; grade 3/4, 0%), fatigue (37%; grade 3/4, 3%), pyrexia (29%; grade 3/4, 0%), and diarrhea (26%; grade 3/4, 0%).
The leading hematologic adverse events were neutropenia (14%; grade 3/4, 14%), with no associated infections; anemia (11%; grade 3/4, 6%); and thrombocytopenia (6%; grade 3/4, 6%), with no associated bleeding.
The overall response rate was 45% (44% in the B-NHL cohort and 50% in the CLL cohort); the majority of responses were partial responses. Notably, the rate was 31% among the subset of patients who had rituximab-refractory disease.
The median duration of response to ublituximab was 9.2 months, and the median progression-free survival was 7.7 months.
“Anti-CD20 therapy has demonstrated the greatest benefit in combination, traditionally with multidrug chemotherapy–based regimens,” the investigators noted. “While the introduction of novel targeted therapies has shifted the treatment paradigm of CLL and indolent lymphoma, the activity of these agents is likely to be potentiated by the addition of an anti-CD20 [monoclonal antibody], given their different mechanisms of action.”
In fact, several multidrug, non–chemotherapy-based regimens are showing promising efficacy and milder toxicity in early trials, they pointed out. “In similar fashion, ublituximab is being evaluated for the treatment of NHL or CLL in combination with other agents,” such as the immunomodulator lenalidomide (Revlimid) and the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica).
TG Therapeutics funded the trial. Dr. Sawas disclosed that he receives research funds from TG Therapeutics.
The investigational anti-CD20 monoclonal antibody ublituximab is safe and has good antitumor activity in patients with B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL) who have previously received the anti-CD20 antibody rituximab, results from a phase I/II trial suggest.
Ublituximab is engineered to have a low fucose content. This feature gives it enhanced antibody-dependent cellular cytotoxicity relative to other anti-CD20 antibodies, especially against tumors having low expression of that protein, as may occur in the development of rituximab resistance.
In the trial, nearly half of the 35 patients studied had a complete or partial response to ublituximab, including nearly one-third of those whose disease was refractory to rituximab (Rituxan) (Br J Haematol. 2017 Apr;177[2]:243-53). The main adverse events were infusion-related reactions, fatigue, pyrexia, and diarrhea, but almost all were lower grade.
“Ublituximab was well tolerated and efficacious in a heterogeneous and highly rituximab–pretreated patient population,” said the investigators, who were led by Ahmed Sawas, MD, at the Center for Lymphoid Malignancies, Columbia University Medical Center, N.Y.
The observed response rate is much the same as those seen with two other anti-CD20 antibodies – obinutuzumab (Gazyva)and ofatumumab (Arzerra)– in similar patient populations, and ublituximab may have advantages in terms of fewer higher-grade infusion-related reactions and shorter infusion time.
“Enhanced anti-CD20 [monoclonal antibodies] that are well tolerated and active in rituximab-resistant disease can provide meaningful clinical benefit to patients with limited treatment options,” the investigators noted.
The trial enrolled 27 patients with B-NHL and 8 patients with CLL (or small lymphocytic lymphoma) who had rituximab-refractory disease (defined by progression on or within 6 months of receiving that agent) or rituximab-relapsed disease (defined by progression more than 6 months after receiving it). They had received a median of three prior therapies.
The patients were treated on an open-label basis with ublituximab at various doses as induction therapy (3-4 weekly infusions during cycles 1 and 2) and then as maintenance therapy (monthly during cycles 3-5, then once every 3 months for up to 2 years). All patients received an oral antihistamine and steroids before infusions.
By the end of the trial, 60% of patients had discontinued treatment because of progression; 23% had discontinued because of adverse events, physician decision, or other reasons; and the remaining 17% had received all planned treatment, Dr. Sawas and his coinvestigators reported.
None of the patients experienced dose-limiting toxicities or unexpected adverse events. The rate of any-grade adverse events was 100%, and the rate specifically of grade 3/4 adverse events was 49%. The rate of serious adverse events (most commonly pneumonia) was 37%.
The leading nonhematologic adverse events were infusion-related reactions (40%; grade 3/4, 0%), fatigue (37%; grade 3/4, 3%), pyrexia (29%; grade 3/4, 0%), and diarrhea (26%; grade 3/4, 0%).
The leading hematologic adverse events were neutropenia (14%; grade 3/4, 14%), with no associated infections; anemia (11%; grade 3/4, 6%); and thrombocytopenia (6%; grade 3/4, 6%), with no associated bleeding.
The overall response rate was 45% (44% in the B-NHL cohort and 50% in the CLL cohort); the majority of responses were partial responses. Notably, the rate was 31% among the subset of patients who had rituximab-refractory disease.
The median duration of response to ublituximab was 9.2 months, and the median progression-free survival was 7.7 months.
“Anti-CD20 therapy has demonstrated the greatest benefit in combination, traditionally with multidrug chemotherapy–based regimens,” the investigators noted. “While the introduction of novel targeted therapies has shifted the treatment paradigm of CLL and indolent lymphoma, the activity of these agents is likely to be potentiated by the addition of an anti-CD20 [monoclonal antibody], given their different mechanisms of action.”
In fact, several multidrug, non–chemotherapy-based regimens are showing promising efficacy and milder toxicity in early trials, they pointed out. “In similar fashion, ublituximab is being evaluated for the treatment of NHL or CLL in combination with other agents,” such as the immunomodulator lenalidomide (Revlimid) and the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica).
TG Therapeutics funded the trial. Dr. Sawas disclosed that he receives research funds from TG Therapeutics.
The investigational anti-CD20 monoclonal antibody ublituximab is safe and has good antitumor activity in patients with B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukemia (CLL) who have previously received the anti-CD20 antibody rituximab, results from a phase I/II trial suggest.
Ublituximab is engineered to have a low fucose content. This feature gives it enhanced antibody-dependent cellular cytotoxicity relative to other anti-CD20 antibodies, especially against tumors having low expression of that protein, as may occur in the development of rituximab resistance.
In the trial, nearly half of the 35 patients studied had a complete or partial response to ublituximab, including nearly one-third of those whose disease was refractory to rituximab (Rituxan) (Br J Haematol. 2017 Apr;177[2]:243-53). The main adverse events were infusion-related reactions, fatigue, pyrexia, and diarrhea, but almost all were lower grade.
“Ublituximab was well tolerated and efficacious in a heterogeneous and highly rituximab–pretreated patient population,” said the investigators, who were led by Ahmed Sawas, MD, at the Center for Lymphoid Malignancies, Columbia University Medical Center, N.Y.
The observed response rate is much the same as those seen with two other anti-CD20 antibodies – obinutuzumab (Gazyva)and ofatumumab (Arzerra)– in similar patient populations, and ublituximab may have advantages in terms of fewer higher-grade infusion-related reactions and shorter infusion time.
“Enhanced anti-CD20 [monoclonal antibodies] that are well tolerated and active in rituximab-resistant disease can provide meaningful clinical benefit to patients with limited treatment options,” the investigators noted.
The trial enrolled 27 patients with B-NHL and 8 patients with CLL (or small lymphocytic lymphoma) who had rituximab-refractory disease (defined by progression on or within 6 months of receiving that agent) or rituximab-relapsed disease (defined by progression more than 6 months after receiving it). They had received a median of three prior therapies.
The patients were treated on an open-label basis with ublituximab at various doses as induction therapy (3-4 weekly infusions during cycles 1 and 2) and then as maintenance therapy (monthly during cycles 3-5, then once every 3 months for up to 2 years). All patients received an oral antihistamine and steroids before infusions.
By the end of the trial, 60% of patients had discontinued treatment because of progression; 23% had discontinued because of adverse events, physician decision, or other reasons; and the remaining 17% had received all planned treatment, Dr. Sawas and his coinvestigators reported.
None of the patients experienced dose-limiting toxicities or unexpected adverse events. The rate of any-grade adverse events was 100%, and the rate specifically of grade 3/4 adverse events was 49%. The rate of serious adverse events (most commonly pneumonia) was 37%.
The leading nonhematologic adverse events were infusion-related reactions (40%; grade 3/4, 0%), fatigue (37%; grade 3/4, 3%), pyrexia (29%; grade 3/4, 0%), and diarrhea (26%; grade 3/4, 0%).
The leading hematologic adverse events were neutropenia (14%; grade 3/4, 14%), with no associated infections; anemia (11%; grade 3/4, 6%); and thrombocytopenia (6%; grade 3/4, 6%), with no associated bleeding.
The overall response rate was 45% (44% in the B-NHL cohort and 50% in the CLL cohort); the majority of responses were partial responses. Notably, the rate was 31% among the subset of patients who had rituximab-refractory disease.
The median duration of response to ublituximab was 9.2 months, and the median progression-free survival was 7.7 months.
“Anti-CD20 therapy has demonstrated the greatest benefit in combination, traditionally with multidrug chemotherapy–based regimens,” the investigators noted. “While the introduction of novel targeted therapies has shifted the treatment paradigm of CLL and indolent lymphoma, the activity of these agents is likely to be potentiated by the addition of an anti-CD20 [monoclonal antibody], given their different mechanisms of action.”
In fact, several multidrug, non–chemotherapy-based regimens are showing promising efficacy and milder toxicity in early trials, they pointed out. “In similar fashion, ublituximab is being evaluated for the treatment of NHL or CLL in combination with other agents,” such as the immunomodulator lenalidomide (Revlimid) and the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica).
TG Therapeutics funded the trial. Dr. Sawas disclosed that he receives research funds from TG Therapeutics.
Key clinical point:
Major finding: The overall response rate was 45%. There were no dose-limiting toxicities; main adverse events of any grade were infusion-related reactions (40%), fatigue (37%), pyrexia (29%), and diarrhea (26%).
Data source: A phase I/II trial among 35 patients with B-NHL or CLL who had previously received rituximab.
Disclosures: TG Therapeutics funded the trial. Dr. Sawas disclosed that he receives research funds from TG Therapeutics.
Walking can benefit advanced cancer patients
Walking for 30 minutes 3 times a week can improve quality of life for patients with advanced cancer, according to research published in BMJ Open.
The study indicated that some patients with advanced cancer may not be able to commit to weekly walks with a group of fellow patients.
However, some patients enjoyed walking in groups, and most reported benefits from regular walks, whether taken alone or with others.
“Findings from this important study show that exercise is valued by, suitable for, and beneficial to people with advanced cancer,” said study author Emma Ream, RN, PhD, of the University of Surrey in the UK.
“Rather than shying away from exercise, people with advanced disease should be encouraged to be more active and incorporate exercise into their daily lives where possible.”
One hundred and ten patients with advanced cancer were eligible to participate in this study, but 49 (47%) declined, primarily because of work commitments. Patients said they could not commit to a weekly walking group.
The 42 patients who did participate in this study were divided into 2 groups.
Group 1 (n=21) received coaching, which included a short motivational interview, as well as the recommendation to walk for at least 30 minutes on alternate days and attend a volunteer-led group walk weekly.
Patients in group 2 (n=21) were encouraged to maintain their current level of activity.
Nineteen participants (45%) withdrew from the study—11 in group 1 and 8 in group 2. In general, patients did not provide reasons for withdrawal. However, 2 patients were too unwell to participate, and 2 patients died during the study.
At 6, 12, and 24 weeks, scores on quality of life questionnaires were not significantly different between groups 1 and 2.
However, in interviews, patients in group 1 said they felt walking provided physical, emotional, and psychological benefits, as well as improvements in social well-being and lifestyle.
At 24 weeks, 8 of 9 participants in group 1 said they found the walking intervention useful, and 7 participants said they were satisfied with it.
Some patients said walking improved their attitude toward their illness and spoke of the social benefits of participating in group walks.
But other patients were dissatisfied with the walking groups. They reported accessibility issues and a dislike of group activities. One younger individual felt the group was more appropriate for older patients.
“This study is a first step towards exploring how walking can help people living with advanced cancer,” said study author Jo Armes, RGN, PhD, of King’s College London in the UK.
“Walking is a free and accessible form of physical activity, and patients reported that it made a real difference to their quality of life. Further research is needed with a larger number of people to provide definitive evidence that walking improves both health outcomes and social and emotional wellbeing in this group of people.”
Walking for 30 minutes 3 times a week can improve quality of life for patients with advanced cancer, according to research published in BMJ Open.
The study indicated that some patients with advanced cancer may not be able to commit to weekly walks with a group of fellow patients.
However, some patients enjoyed walking in groups, and most reported benefits from regular walks, whether taken alone or with others.
“Findings from this important study show that exercise is valued by, suitable for, and beneficial to people with advanced cancer,” said study author Emma Ream, RN, PhD, of the University of Surrey in the UK.
“Rather than shying away from exercise, people with advanced disease should be encouraged to be more active and incorporate exercise into their daily lives where possible.”
One hundred and ten patients with advanced cancer were eligible to participate in this study, but 49 (47%) declined, primarily because of work commitments. Patients said they could not commit to a weekly walking group.
The 42 patients who did participate in this study were divided into 2 groups.
Group 1 (n=21) received coaching, which included a short motivational interview, as well as the recommendation to walk for at least 30 minutes on alternate days and attend a volunteer-led group walk weekly.
Patients in group 2 (n=21) were encouraged to maintain their current level of activity.
Nineteen participants (45%) withdrew from the study—11 in group 1 and 8 in group 2. In general, patients did not provide reasons for withdrawal. However, 2 patients were too unwell to participate, and 2 patients died during the study.
At 6, 12, and 24 weeks, scores on quality of life questionnaires were not significantly different between groups 1 and 2.
However, in interviews, patients in group 1 said they felt walking provided physical, emotional, and psychological benefits, as well as improvements in social well-being and lifestyle.
At 24 weeks, 8 of 9 participants in group 1 said they found the walking intervention useful, and 7 participants said they were satisfied with it.
Some patients said walking improved their attitude toward their illness and spoke of the social benefits of participating in group walks.
But other patients were dissatisfied with the walking groups. They reported accessibility issues and a dislike of group activities. One younger individual felt the group was more appropriate for older patients.
“This study is a first step towards exploring how walking can help people living with advanced cancer,” said study author Jo Armes, RGN, PhD, of King’s College London in the UK.
“Walking is a free and accessible form of physical activity, and patients reported that it made a real difference to their quality of life. Further research is needed with a larger number of people to provide definitive evidence that walking improves both health outcomes and social and emotional wellbeing in this group of people.”
Walking for 30 minutes 3 times a week can improve quality of life for patients with advanced cancer, according to research published in BMJ Open.
The study indicated that some patients with advanced cancer may not be able to commit to weekly walks with a group of fellow patients.
However, some patients enjoyed walking in groups, and most reported benefits from regular walks, whether taken alone or with others.
“Findings from this important study show that exercise is valued by, suitable for, and beneficial to people with advanced cancer,” said study author Emma Ream, RN, PhD, of the University of Surrey in the UK.
“Rather than shying away from exercise, people with advanced disease should be encouraged to be more active and incorporate exercise into their daily lives where possible.”
One hundred and ten patients with advanced cancer were eligible to participate in this study, but 49 (47%) declined, primarily because of work commitments. Patients said they could not commit to a weekly walking group.
The 42 patients who did participate in this study were divided into 2 groups.
Group 1 (n=21) received coaching, which included a short motivational interview, as well as the recommendation to walk for at least 30 minutes on alternate days and attend a volunteer-led group walk weekly.
Patients in group 2 (n=21) were encouraged to maintain their current level of activity.
Nineteen participants (45%) withdrew from the study—11 in group 1 and 8 in group 2. In general, patients did not provide reasons for withdrawal. However, 2 patients were too unwell to participate, and 2 patients died during the study.
At 6, 12, and 24 weeks, scores on quality of life questionnaires were not significantly different between groups 1 and 2.
However, in interviews, patients in group 1 said they felt walking provided physical, emotional, and psychological benefits, as well as improvements in social well-being and lifestyle.
At 24 weeks, 8 of 9 participants in group 1 said they found the walking intervention useful, and 7 participants said they were satisfied with it.
Some patients said walking improved their attitude toward their illness and spoke of the social benefits of participating in group walks.
But other patients were dissatisfied with the walking groups. They reported accessibility issues and a dislike of group activities. One younger individual felt the group was more appropriate for older patients.
“This study is a first step towards exploring how walking can help people living with advanced cancer,” said study author Jo Armes, RGN, PhD, of King’s College London in the UK.
“Walking is a free and accessible form of physical activity, and patients reported that it made a real difference to their quality of life. Further research is needed with a larger number of people to provide definitive evidence that walking improves both health outcomes and social and emotional wellbeing in this group of people.”
Site of care may impact survival for AYAs with ALL, AML
Receiving treatment at specialized cancer centers may improve survival for adolescents and young adults (AYAs) with acute leukemia, according to a study published in Cancer Epidemiology, Biomarkers & Prevention.
The study showed that, when patients were treated at specialized cancer centers, survival rates were similar for younger AYAs and children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
However, older AYAs did not appear to reap the same survival benefit from receiving treatment at a specialized cancer center.
And AYAs of all ages had significantly worse survival than children if they were not treated at specialized cancer centers.
AYAs (patients ages 15 to 39) with ALL and AML have significantly worse survival outcomes than children ages 14 and under, according to study author Julie Wolfson, MD, of the University of Alabama at Birmingham.
“A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer,” she added. “We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes.”
Dr Wolfson and her colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39.
Patients were said to have been treated at a specialized cancer center if, at any age, they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers (CCC) in Los Angeles County or if, at the age of 21 or younger, they were cared for at any of the Children’s Oncology Group (COG) sites not designated a Comprehensive Cancer Center.
Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA.
Seventy percent of the children with ALL and 30% of the AYAs with ALL were treated at CCC/COG sites. Seventy-four percent of the children with AML and 22% of the AYAs with AML were treated at CCC/COG sites.
Results in ALL
AYAs diagnosed with ALL at ages 15 to 21 and 22 to 29 who were treated at CCC/COG sites had comparable survival to children who were diagnosed with ALL from ages 10 to 14 and treated at CCC/COG sites. The hazard ratios (HRs) were 1.3 for the 15-21 age group (P=0.3) and 1.2 for the 22-29 age group (P=0.8).
The reference group for this analysis was 10- to 14-year-olds treated at CCC/COG sites because the researchers excluded data from children with ALL ages 1 to 9. These patients were excluded because they have significantly better survival than the other groups, potentially as a result of different disease biology.
The researchers also found that treatment at CCC/COG sites did not improve survival for 30- to 39-year-olds with ALL. The HR for them was 3.4 (P<0.001).
Likewise, all AYAs with ALL who were not treated at CCC/COG sites had worse survival than 10- to 14-year-olds treated at CCC/COG sites. The HRs were 1.9 for the 15-21 age group (P=0.005), 2.6 for the 22-29 age group (P<0.001), and 3.0 for the 30-39 age group (P<0.001).
Results in AML
For AML patients, the reference group was 1- to 14-year-olds treated at CCC/COG sites. Compared to these patients, 15- to 21-year-olds not treated at CCC/COG sites had an increased hazard of death (HR=1.7, P=0.02), whereas 15- to 21-year-olds treated at CCC/COG sites did not (HR=1.3; P=0.4).
All 22- to 39-year-olds, regardless of the site of care, had an increased hazard of death compared to the children treated at CCC/COG sites. The HR was 3.4 (P<0.001) for 22- to 39-year-olds treated at CCC/COG sites, and the HR was 3.0 (P<0.001) for 22- to 39-year-olds not treated at CCC/COG sites.
“The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals,” Dr Wolfson said.
“The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy.
Receiving treatment at specialized cancer centers may improve survival for adolescents and young adults (AYAs) with acute leukemia, according to a study published in Cancer Epidemiology, Biomarkers & Prevention.
The study showed that, when patients were treated at specialized cancer centers, survival rates were similar for younger AYAs and children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
However, older AYAs did not appear to reap the same survival benefit from receiving treatment at a specialized cancer center.
And AYAs of all ages had significantly worse survival than children if they were not treated at specialized cancer centers.
AYAs (patients ages 15 to 39) with ALL and AML have significantly worse survival outcomes than children ages 14 and under, according to study author Julie Wolfson, MD, of the University of Alabama at Birmingham.
“A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer,” she added. “We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes.”
Dr Wolfson and her colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39.
Patients were said to have been treated at a specialized cancer center if, at any age, they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers (CCC) in Los Angeles County or if, at the age of 21 or younger, they were cared for at any of the Children’s Oncology Group (COG) sites not designated a Comprehensive Cancer Center.
Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA.
Seventy percent of the children with ALL and 30% of the AYAs with ALL were treated at CCC/COG sites. Seventy-four percent of the children with AML and 22% of the AYAs with AML were treated at CCC/COG sites.
Results in ALL
AYAs diagnosed with ALL at ages 15 to 21 and 22 to 29 who were treated at CCC/COG sites had comparable survival to children who were diagnosed with ALL from ages 10 to 14 and treated at CCC/COG sites. The hazard ratios (HRs) were 1.3 for the 15-21 age group (P=0.3) and 1.2 for the 22-29 age group (P=0.8).
The reference group for this analysis was 10- to 14-year-olds treated at CCC/COG sites because the researchers excluded data from children with ALL ages 1 to 9. These patients were excluded because they have significantly better survival than the other groups, potentially as a result of different disease biology.
The researchers also found that treatment at CCC/COG sites did not improve survival for 30- to 39-year-olds with ALL. The HR for them was 3.4 (P<0.001).
Likewise, all AYAs with ALL who were not treated at CCC/COG sites had worse survival than 10- to 14-year-olds treated at CCC/COG sites. The HRs were 1.9 for the 15-21 age group (P=0.005), 2.6 for the 22-29 age group (P<0.001), and 3.0 for the 30-39 age group (P<0.001).
Results in AML
For AML patients, the reference group was 1- to 14-year-olds treated at CCC/COG sites. Compared to these patients, 15- to 21-year-olds not treated at CCC/COG sites had an increased hazard of death (HR=1.7, P=0.02), whereas 15- to 21-year-olds treated at CCC/COG sites did not (HR=1.3; P=0.4).
All 22- to 39-year-olds, regardless of the site of care, had an increased hazard of death compared to the children treated at CCC/COG sites. The HR was 3.4 (P<0.001) for 22- to 39-year-olds treated at CCC/COG sites, and the HR was 3.0 (P<0.001) for 22- to 39-year-olds not treated at CCC/COG sites.
“The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals,” Dr Wolfson said.
“The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy.
Receiving treatment at specialized cancer centers may improve survival for adolescents and young adults (AYAs) with acute leukemia, according to a study published in Cancer Epidemiology, Biomarkers & Prevention.
The study showed that, when patients were treated at specialized cancer centers, survival rates were similar for younger AYAs and children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
However, older AYAs did not appear to reap the same survival benefit from receiving treatment at a specialized cancer center.
And AYAs of all ages had significantly worse survival than children if they were not treated at specialized cancer centers.
AYAs (patients ages 15 to 39) with ALL and AML have significantly worse survival outcomes than children ages 14 and under, according to study author Julie Wolfson, MD, of the University of Alabama at Birmingham.
“A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer,” she added. “We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes.”
Dr Wolfson and her colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39.
Patients were said to have been treated at a specialized cancer center if, at any age, they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers (CCC) in Los Angeles County or if, at the age of 21 or younger, they were cared for at any of the Children’s Oncology Group (COG) sites not designated a Comprehensive Cancer Center.
Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA.
Seventy percent of the children with ALL and 30% of the AYAs with ALL were treated at CCC/COG sites. Seventy-four percent of the children with AML and 22% of the AYAs with AML were treated at CCC/COG sites.
Results in ALL
AYAs diagnosed with ALL at ages 15 to 21 and 22 to 29 who were treated at CCC/COG sites had comparable survival to children who were diagnosed with ALL from ages 10 to 14 and treated at CCC/COG sites. The hazard ratios (HRs) were 1.3 for the 15-21 age group (P=0.3) and 1.2 for the 22-29 age group (P=0.8).
The reference group for this analysis was 10- to 14-year-olds treated at CCC/COG sites because the researchers excluded data from children with ALL ages 1 to 9. These patients were excluded because they have significantly better survival than the other groups, potentially as a result of different disease biology.
The researchers also found that treatment at CCC/COG sites did not improve survival for 30- to 39-year-olds with ALL. The HR for them was 3.4 (P<0.001).
Likewise, all AYAs with ALL who were not treated at CCC/COG sites had worse survival than 10- to 14-year-olds treated at CCC/COG sites. The HRs were 1.9 for the 15-21 age group (P=0.005), 2.6 for the 22-29 age group (P<0.001), and 3.0 for the 30-39 age group (P<0.001).
Results in AML
For AML patients, the reference group was 1- to 14-year-olds treated at CCC/COG sites. Compared to these patients, 15- to 21-year-olds not treated at CCC/COG sites had an increased hazard of death (HR=1.7, P=0.02), whereas 15- to 21-year-olds treated at CCC/COG sites did not (HR=1.3; P=0.4).
All 22- to 39-year-olds, regardless of the site of care, had an increased hazard of death compared to the children treated at CCC/COG sites. The HR was 3.4 (P<0.001) for 22- to 39-year-olds treated at CCC/COG sites, and the HR was 3.0 (P<0.001) for 22- to 39-year-olds not treated at CCC/COG sites.
“The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals,” Dr Wolfson said.
“The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy.
Group ranks TKIs according to cardiotoxicity
Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.
The team found they could accurately identify those TKIs already known to be the most dangerous.
The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.
“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.
“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”
Dr Wu and his colleagues described this research in Science Translational Medicine.
The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.
The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.
Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.
The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.
High cardiotoxicity
Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.
These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.
Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.
This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.
They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.
“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”
Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.
The team found they could accurately identify those TKIs already known to be the most dangerous.
The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.
“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.
“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”
Dr Wu and his colleagues described this research in Science Translational Medicine.
The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.
The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.
Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.
The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.
High cardiotoxicity
Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.
These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.
Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.
This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.
They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.
“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”
Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.
The team found they could accurately identify those TKIs already known to be the most dangerous.
The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.
“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.
“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”
Dr Wu and his colleagues described this research in Science Translational Medicine.
The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.
The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.
Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.
The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.
High cardiotoxicity
Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.
These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.
Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.
This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.
They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.
“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”
Proximity to oil, gas wells linked to ALL
A pumpjack is used to lift
liquid from an oil well.
Photo by Eric Kounce
Living in an area of high-density oil and gas development may increase a young person’s risk of developing acute lymphoblastic leukemia (ALL), according to research published in PLOS ONE.
The study showed that children and young adults in Colorado who had been diagnosed with ALL were more likely than young people with non-hematologic cancers to live in areas of high-density oil and gas development.
However, there was no such association for young people with non-Hodgkin lymphoma (NHL).
“Over 378,000 Coloradans and millions of Americans currently live within a mile of at least one oil and gas well, and petroleum development continues to expand into residential areas,” said study author Lisa McKenzie, PhD, of the University of Colorado Anschutz Campus in Aurora.
“The findings from our registry-based, case-control study indicate that young Coloradans diagnosed with one type of childhood leukemia are more likely to live in the densest areas of oil and gas sites. More comprehensive research that can address our study’s limitations is needed to understand and explain these results.”
Dr McKenzie and her colleagues said they conducted this study because oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas.
The team wanted to determine whether living near areas of oil and gas development was associated with risk for hematologic cancers. So they analyzed data from the Colorado Central Cancer Registry and the Colorado Oil and Gas Information System.
The study included 743 subjects, ages 0 to 24, living in rural Colorado and diagnosed with cancer between 2001 and 2013. This included 87 ALL cases, 50 NHL cases, and 528 controls with non-hematologic cancers. (Other hematologic malignancies were not included in the analysis due to small numbers.)
Data analysis
The researchers used information from the Colorado Oil and Gas Information System to build a geocoded dataset with coordinates of all oil and gas wells in rural Colorado and determined dates for when each well was active.
Geocoded residential addresses of cancer patients at the time of diagnosis were linked to active well locations in the year of diagnosis and active well locations in each of the 10 years preceding the cancer diagnosis.
The researchers then took the inverse of each distance and summed the inverse distances to calculate inverse distance weighted (IDW) oil and gas well counts within a 16.1 km radius of each participant’s residence at cancer diagnosis for each of the 10 years prior to the date of diagnosis. (The IDW well count method gives greater weight to the wells nearer the home.)
The team used logistic regression to estimate associations for cancers across IDW well count tertiles. The first tertile had less than 4.9 wells per 1.6 km, the second had 4.9 to 33.6 wells per 1.6 km, and the third had more than 33.6 wells per 1.6 km.
Results
The researchers found an increase in the odds of living near oil and gas development at the time of ALL diagnosis, even after adjusting for age, race, gender, income, elevation, and year of cancer diagnosis.
ALL patients ages 0 to 24 were twice as likely as controls to live in the densest area of active oil and gas wells (highest IDW well count tertile).
ALL patients ages 5 to 24 were 4.6 times more likely than controls to live in areas included in the highest IDW well count tertile.
However, there was no significant association between ALL and proximity to oil and gas development in ALL patients ages 0 to 4. The adjusted odds ratio was 0.51 for the highest IDW well count tertile.
Likewise, there were no significant associations between density of oil and gas development and NHL. The adjusted odds ratio was 0.99 for the highest IDW well count tertile.
Limitations and next steps
The researchers said this study was limited by the low occurrence of ALL and NHL in rural Colorado, lack of specific age at cancer diagnosis, and the fact that all study participants had been diagnosed with cancer.
In addition, the study was limited by the lack of information on specific activities at the well sites, place of residence before cancer diagnosis, other sources of pollution around the residence, and individual characteristics such as common infections and family history of cancer.
The team said future research should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest such as benzene, near homes, schools, and day care centers.
They recommended that such research consider specific ages and residential histories, compare cases to controls without cancer, and address other potential confounders and and environmental stressors.
A pumpjack is used to lift
liquid from an oil well.
Photo by Eric Kounce
Living in an area of high-density oil and gas development may increase a young person’s risk of developing acute lymphoblastic leukemia (ALL), according to research published in PLOS ONE.
The study showed that children and young adults in Colorado who had been diagnosed with ALL were more likely than young people with non-hematologic cancers to live in areas of high-density oil and gas development.
However, there was no such association for young people with non-Hodgkin lymphoma (NHL).
“Over 378,000 Coloradans and millions of Americans currently live within a mile of at least one oil and gas well, and petroleum development continues to expand into residential areas,” said study author Lisa McKenzie, PhD, of the University of Colorado Anschutz Campus in Aurora.
“The findings from our registry-based, case-control study indicate that young Coloradans diagnosed with one type of childhood leukemia are more likely to live in the densest areas of oil and gas sites. More comprehensive research that can address our study’s limitations is needed to understand and explain these results.”
Dr McKenzie and her colleagues said they conducted this study because oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas.
The team wanted to determine whether living near areas of oil and gas development was associated with risk for hematologic cancers. So they analyzed data from the Colorado Central Cancer Registry and the Colorado Oil and Gas Information System.
The study included 743 subjects, ages 0 to 24, living in rural Colorado and diagnosed with cancer between 2001 and 2013. This included 87 ALL cases, 50 NHL cases, and 528 controls with non-hematologic cancers. (Other hematologic malignancies were not included in the analysis due to small numbers.)
Data analysis
The researchers used information from the Colorado Oil and Gas Information System to build a geocoded dataset with coordinates of all oil and gas wells in rural Colorado and determined dates for when each well was active.
Geocoded residential addresses of cancer patients at the time of diagnosis were linked to active well locations in the year of diagnosis and active well locations in each of the 10 years preceding the cancer diagnosis.
The researchers then took the inverse of each distance and summed the inverse distances to calculate inverse distance weighted (IDW) oil and gas well counts within a 16.1 km radius of each participant’s residence at cancer diagnosis for each of the 10 years prior to the date of diagnosis. (The IDW well count method gives greater weight to the wells nearer the home.)
The team used logistic regression to estimate associations for cancers across IDW well count tertiles. The first tertile had less than 4.9 wells per 1.6 km, the second had 4.9 to 33.6 wells per 1.6 km, and the third had more than 33.6 wells per 1.6 km.
Results
The researchers found an increase in the odds of living near oil and gas development at the time of ALL diagnosis, even after adjusting for age, race, gender, income, elevation, and year of cancer diagnosis.
ALL patients ages 0 to 24 were twice as likely as controls to live in the densest area of active oil and gas wells (highest IDW well count tertile).
ALL patients ages 5 to 24 were 4.6 times more likely than controls to live in areas included in the highest IDW well count tertile.
However, there was no significant association between ALL and proximity to oil and gas development in ALL patients ages 0 to 4. The adjusted odds ratio was 0.51 for the highest IDW well count tertile.
Likewise, there were no significant associations between density of oil and gas development and NHL. The adjusted odds ratio was 0.99 for the highest IDW well count tertile.
Limitations and next steps
The researchers said this study was limited by the low occurrence of ALL and NHL in rural Colorado, lack of specific age at cancer diagnosis, and the fact that all study participants had been diagnosed with cancer.
In addition, the study was limited by the lack of information on specific activities at the well sites, place of residence before cancer diagnosis, other sources of pollution around the residence, and individual characteristics such as common infections and family history of cancer.
The team said future research should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest such as benzene, near homes, schools, and day care centers.
They recommended that such research consider specific ages and residential histories, compare cases to controls without cancer, and address other potential confounders and and environmental stressors.
A pumpjack is used to lift
liquid from an oil well.
Photo by Eric Kounce
Living in an area of high-density oil and gas development may increase a young person’s risk of developing acute lymphoblastic leukemia (ALL), according to research published in PLOS ONE.
The study showed that children and young adults in Colorado who had been diagnosed with ALL were more likely than young people with non-hematologic cancers to live in areas of high-density oil and gas development.
However, there was no such association for young people with non-Hodgkin lymphoma (NHL).
“Over 378,000 Coloradans and millions of Americans currently live within a mile of at least one oil and gas well, and petroleum development continues to expand into residential areas,” said study author Lisa McKenzie, PhD, of the University of Colorado Anschutz Campus in Aurora.
“The findings from our registry-based, case-control study indicate that young Coloradans diagnosed with one type of childhood leukemia are more likely to live in the densest areas of oil and gas sites. More comprehensive research that can address our study’s limitations is needed to understand and explain these results.”
Dr McKenzie and her colleagues said they conducted this study because oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas.
The team wanted to determine whether living near areas of oil and gas development was associated with risk for hematologic cancers. So they analyzed data from the Colorado Central Cancer Registry and the Colorado Oil and Gas Information System.
The study included 743 subjects, ages 0 to 24, living in rural Colorado and diagnosed with cancer between 2001 and 2013. This included 87 ALL cases, 50 NHL cases, and 528 controls with non-hematologic cancers. (Other hematologic malignancies were not included in the analysis due to small numbers.)
Data analysis
The researchers used information from the Colorado Oil and Gas Information System to build a geocoded dataset with coordinates of all oil and gas wells in rural Colorado and determined dates for when each well was active.
Geocoded residential addresses of cancer patients at the time of diagnosis were linked to active well locations in the year of diagnosis and active well locations in each of the 10 years preceding the cancer diagnosis.
The researchers then took the inverse of each distance and summed the inverse distances to calculate inverse distance weighted (IDW) oil and gas well counts within a 16.1 km radius of each participant’s residence at cancer diagnosis for each of the 10 years prior to the date of diagnosis. (The IDW well count method gives greater weight to the wells nearer the home.)
The team used logistic regression to estimate associations for cancers across IDW well count tertiles. The first tertile had less than 4.9 wells per 1.6 km, the second had 4.9 to 33.6 wells per 1.6 km, and the third had more than 33.6 wells per 1.6 km.
Results
The researchers found an increase in the odds of living near oil and gas development at the time of ALL diagnosis, even after adjusting for age, race, gender, income, elevation, and year of cancer diagnosis.
ALL patients ages 0 to 24 were twice as likely as controls to live in the densest area of active oil and gas wells (highest IDW well count tertile).
ALL patients ages 5 to 24 were 4.6 times more likely than controls to live in areas included in the highest IDW well count tertile.
However, there was no significant association between ALL and proximity to oil and gas development in ALL patients ages 0 to 4. The adjusted odds ratio was 0.51 for the highest IDW well count tertile.
Likewise, there were no significant associations between density of oil and gas development and NHL. The adjusted odds ratio was 0.99 for the highest IDW well count tertile.
Limitations and next steps
The researchers said this study was limited by the low occurrence of ALL and NHL in rural Colorado, lack of specific age at cancer diagnosis, and the fact that all study participants had been diagnosed with cancer.
In addition, the study was limited by the lack of information on specific activities at the well sites, place of residence before cancer diagnosis, other sources of pollution around the residence, and individual characteristics such as common infections and family history of cancer.
The team said future research should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest such as benzene, near homes, schools, and day care centers.
They recommended that such research consider specific ages and residential histories, compare cases to controls without cancer, and address other potential confounders and and environmental stressors.
Styrene exposure linked to myeloid leukemia, HL
A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.
The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.
On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).
The research was published in Epidemiology.
“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.
“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”
In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.
For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.
There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.
As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.
For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.
The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.
For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.
The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.
The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.
The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.
There were no such associations for other cancer sites.
A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.
The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.
On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).
The research was published in Epidemiology.
“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.
“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”
In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.
For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.
There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.
As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.
For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.
The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.
For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.
The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.
The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.
The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.
There were no such associations for other cancer sites.
A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.
The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.
On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).
The research was published in Epidemiology.
“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.
“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”
In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.
For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.
There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.
As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.
For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.
The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.
For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.
The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.
The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.
The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.
There were no such associations for other cancer sites.
Cancer survivors report pros and cons of telehealth
Photo by Daniel Sone
Cancer survivors report a range of benefits and detriments related to telehealth, according to research published in the Journal of Medical Internet Research.
Telehealth is the use of technology to provide remote, personalized healthcare to patients.
Telehealth services allow patients to have meetings and follow-up consultations with healthcare professionals either on the phone or through online services at a time that suits the patients.
Anna Cox, PhD, of the University of Surrey in the UK, and her colleagues examined 22 studies, published between 2006 and 2016, that reported cancer patients’ direct views on their experience of telehealth.
Some of the cancer survivors studied reported their appreciation of the flexibility and convenience of telehealth, which enabled them to engage with healthcare providers with minimum disruption to their lives and in a comfortable, familiar environment.
“Our research found that cancer survivors wanted to get back to their daily lives as quickly as possible,” Dr Cox said. “Telehealth helped facilitate this, as it removed the often burdensome visits to hospital and enabled the integration of care into daily routines.”
However, not all subjects viewed telehealth as a convenience. Of the Internet-based interventions studied, 2 were perceived as an extra burden, and 1 was considered too time-consuming.
In addition, some study participants viewed telehealth as an impersonal service that did not allow them to meet their healthcare team in person.
On the other hand, the invisibility and perceived anonymity that telehealth provided sometimes reduced cancer survivors’ sense of vulnerability and enabled them to raise concerns remotely that they would not have wanted to discuss face-to-face.
And, in 8 different studies, subjects said telehealth had educated them about ways they could improve or manage their symptoms, or it had raised their awareness of potential issues they might experience.
Unfortunately, some of the cancer survivors studied said they were unable to use telehealth due to personal circumstances, such as hearing issues and lack of computer literacy skills.
“For many cancer survivors, telehealth supported their independence and offered them reassurance,” Dr Cox noted. “However, it is all down to personal preference, as some cancer survivors still preferred traditional methods of care.”
Photo by Daniel Sone
Cancer survivors report a range of benefits and detriments related to telehealth, according to research published in the Journal of Medical Internet Research.
Telehealth is the use of technology to provide remote, personalized healthcare to patients.
Telehealth services allow patients to have meetings and follow-up consultations with healthcare professionals either on the phone or through online services at a time that suits the patients.
Anna Cox, PhD, of the University of Surrey in the UK, and her colleagues examined 22 studies, published between 2006 and 2016, that reported cancer patients’ direct views on their experience of telehealth.
Some of the cancer survivors studied reported their appreciation of the flexibility and convenience of telehealth, which enabled them to engage with healthcare providers with minimum disruption to their lives and in a comfortable, familiar environment.
“Our research found that cancer survivors wanted to get back to their daily lives as quickly as possible,” Dr Cox said. “Telehealth helped facilitate this, as it removed the often burdensome visits to hospital and enabled the integration of care into daily routines.”
However, not all subjects viewed telehealth as a convenience. Of the Internet-based interventions studied, 2 were perceived as an extra burden, and 1 was considered too time-consuming.
In addition, some study participants viewed telehealth as an impersonal service that did not allow them to meet their healthcare team in person.
On the other hand, the invisibility and perceived anonymity that telehealth provided sometimes reduced cancer survivors’ sense of vulnerability and enabled them to raise concerns remotely that they would not have wanted to discuss face-to-face.
And, in 8 different studies, subjects said telehealth had educated them about ways they could improve or manage their symptoms, or it had raised their awareness of potential issues they might experience.
Unfortunately, some of the cancer survivors studied said they were unable to use telehealth due to personal circumstances, such as hearing issues and lack of computer literacy skills.
“For many cancer survivors, telehealth supported their independence and offered them reassurance,” Dr Cox noted. “However, it is all down to personal preference, as some cancer survivors still preferred traditional methods of care.”
Photo by Daniel Sone
Cancer survivors report a range of benefits and detriments related to telehealth, according to research published in the Journal of Medical Internet Research.
Telehealth is the use of technology to provide remote, personalized healthcare to patients.
Telehealth services allow patients to have meetings and follow-up consultations with healthcare professionals either on the phone or through online services at a time that suits the patients.
Anna Cox, PhD, of the University of Surrey in the UK, and her colleagues examined 22 studies, published between 2006 and 2016, that reported cancer patients’ direct views on their experience of telehealth.
Some of the cancer survivors studied reported their appreciation of the flexibility and convenience of telehealth, which enabled them to engage with healthcare providers with minimum disruption to their lives and in a comfortable, familiar environment.
“Our research found that cancer survivors wanted to get back to their daily lives as quickly as possible,” Dr Cox said. “Telehealth helped facilitate this, as it removed the often burdensome visits to hospital and enabled the integration of care into daily routines.”
However, not all subjects viewed telehealth as a convenience. Of the Internet-based interventions studied, 2 were perceived as an extra burden, and 1 was considered too time-consuming.
In addition, some study participants viewed telehealth as an impersonal service that did not allow them to meet their healthcare team in person.
On the other hand, the invisibility and perceived anonymity that telehealth provided sometimes reduced cancer survivors’ sense of vulnerability and enabled them to raise concerns remotely that they would not have wanted to discuss face-to-face.
And, in 8 different studies, subjects said telehealth had educated them about ways they could improve or manage their symptoms, or it had raised their awareness of potential issues they might experience.
Unfortunately, some of the cancer survivors studied said they were unable to use telehealth due to personal circumstances, such as hearing issues and lack of computer literacy skills.
“For many cancer survivors, telehealth supported their independence and offered them reassurance,” Dr Cox noted. “However, it is all down to personal preference, as some cancer survivors still preferred traditional methods of care.”
B-cell energy levels linked to leukemic transformation
Photo from Business Wire
A pair of transcription factors protect B cells from malignant transformation by keeping the cells’ glucose and energy levels low, according to research published in Nature.
“While transformation to cancer and childhood leukemia takes large amounts of energy, we discovered that low energy levels in B cells protects from malignant transformation toward leukemia and cancer,” said study author Markus Müschen, MD, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California.
“The low energy levels in normal B cells are simply too low to allow transformation to leukemia.”
Dr Müschen and his colleagues found that PAX5 and IKZF1, transcription factors that are critical for early B-cell development, “enforce a state of chronic energy deprivation” that results in constitutive activation of the energy-stress sensor AMPK.
However, dominant-negative mutants of PAX5 and IKZF1 reverse this effect.
Past research has suggested that mutations and deletions in the PAX5 and IKZF1 genes occur in more than 80% of cases of pre-B-cell acute lymphoblastic leukemia (ALL).
In the current study, Dr Müschen and his colleagues found that heterozygous deletion of Pax5 in a mouse model of pre-B ALL greatly increased glucose uptake and ATP levels.
Similarly, when they reconstituted PAX5 and IKZF1 in samples from patients with pre-B ALL, the investigators observed “an energy crisis” that prompted leukemic cell death.
Dr Müschen and his colleagues also performed a CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets. They said this revealed that NR3C1, TXNIP, and CNR2 are central effectors of B-lymphoid restriction of glucose and energy.
To build upon this finding, the investigators tested TXNIP and CNR2 agonists as well as a small-molecule AMPK inhibitor. They found these compounds synergized with glucocorticoids in patient-derived pre-B ALL cells.
The team therefore concluded that TXNIP, CNR2, and AMPK are potential therapeutic targets for pre-B ALL.
The investigators also said the results of this study support a previous finding that obese children with high blood sugar levels are much more likely to develop drug-resistant leukemia than children who are not overweight. So dieting could be an important consideration for children who have survived leukemia.
“Avoiding obesity and excessive energy supply may help to decrease the risk of leukemia relapse,” said study author Lai Chan, PhD, also of City of Hope.
To test that theory, Drs Chan and Müschen and their colleagues plan to perform experiments in animal models to evaluate the efficacy of dietary restriction on patient-derived childhood leukemia cells, and to assess the activity of drugs that reduce leukemia cells’ glucose and energy supply.
“Based on the outcome of these studies, we plan to introduce dietary restriction and/or glucose-restricting drugs into a clinical trial for children who are at risk to develop leukemia relapse,” Dr Müschen said.
Photo from Business Wire
A pair of transcription factors protect B cells from malignant transformation by keeping the cells’ glucose and energy levels low, according to research published in Nature.
“While transformation to cancer and childhood leukemia takes large amounts of energy, we discovered that low energy levels in B cells protects from malignant transformation toward leukemia and cancer,” said study author Markus Müschen, MD, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California.
“The low energy levels in normal B cells are simply too low to allow transformation to leukemia.”
Dr Müschen and his colleagues found that PAX5 and IKZF1, transcription factors that are critical for early B-cell development, “enforce a state of chronic energy deprivation” that results in constitutive activation of the energy-stress sensor AMPK.
However, dominant-negative mutants of PAX5 and IKZF1 reverse this effect.
Past research has suggested that mutations and deletions in the PAX5 and IKZF1 genes occur in more than 80% of cases of pre-B-cell acute lymphoblastic leukemia (ALL).
In the current study, Dr Müschen and his colleagues found that heterozygous deletion of Pax5 in a mouse model of pre-B ALL greatly increased glucose uptake and ATP levels.
Similarly, when they reconstituted PAX5 and IKZF1 in samples from patients with pre-B ALL, the investigators observed “an energy crisis” that prompted leukemic cell death.
Dr Müschen and his colleagues also performed a CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets. They said this revealed that NR3C1, TXNIP, and CNR2 are central effectors of B-lymphoid restriction of glucose and energy.
To build upon this finding, the investigators tested TXNIP and CNR2 agonists as well as a small-molecule AMPK inhibitor. They found these compounds synergized with glucocorticoids in patient-derived pre-B ALL cells.
The team therefore concluded that TXNIP, CNR2, and AMPK are potential therapeutic targets for pre-B ALL.
The investigators also said the results of this study support a previous finding that obese children with high blood sugar levels are much more likely to develop drug-resistant leukemia than children who are not overweight. So dieting could be an important consideration for children who have survived leukemia.
“Avoiding obesity and excessive energy supply may help to decrease the risk of leukemia relapse,” said study author Lai Chan, PhD, also of City of Hope.
To test that theory, Drs Chan and Müschen and their colleagues plan to perform experiments in animal models to evaluate the efficacy of dietary restriction on patient-derived childhood leukemia cells, and to assess the activity of drugs that reduce leukemia cells’ glucose and energy supply.
“Based on the outcome of these studies, we plan to introduce dietary restriction and/or glucose-restricting drugs into a clinical trial for children who are at risk to develop leukemia relapse,” Dr Müschen said.
Photo from Business Wire
A pair of transcription factors protect B cells from malignant transformation by keeping the cells’ glucose and energy levels low, according to research published in Nature.
“While transformation to cancer and childhood leukemia takes large amounts of energy, we discovered that low energy levels in B cells protects from malignant transformation toward leukemia and cancer,” said study author Markus Müschen, MD, PhD, of City of Hope Comprehensive Cancer Center in Duarte, California.
“The low energy levels in normal B cells are simply too low to allow transformation to leukemia.”
Dr Müschen and his colleagues found that PAX5 and IKZF1, transcription factors that are critical for early B-cell development, “enforce a state of chronic energy deprivation” that results in constitutive activation of the energy-stress sensor AMPK.
However, dominant-negative mutants of PAX5 and IKZF1 reverse this effect.
Past research has suggested that mutations and deletions in the PAX5 and IKZF1 genes occur in more than 80% of cases of pre-B-cell acute lymphoblastic leukemia (ALL).
In the current study, Dr Müschen and his colleagues found that heterozygous deletion of Pax5 in a mouse model of pre-B ALL greatly increased glucose uptake and ATP levels.
Similarly, when they reconstituted PAX5 and IKZF1 in samples from patients with pre-B ALL, the investigators observed “an energy crisis” that prompted leukemic cell death.
Dr Müschen and his colleagues also performed a CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets. They said this revealed that NR3C1, TXNIP, and CNR2 are central effectors of B-lymphoid restriction of glucose and energy.
To build upon this finding, the investigators tested TXNIP and CNR2 agonists as well as a small-molecule AMPK inhibitor. They found these compounds synergized with glucocorticoids in patient-derived pre-B ALL cells.
The team therefore concluded that TXNIP, CNR2, and AMPK are potential therapeutic targets for pre-B ALL.
The investigators also said the results of this study support a previous finding that obese children with high blood sugar levels are much more likely to develop drug-resistant leukemia than children who are not overweight. So dieting could be an important consideration for children who have survived leukemia.
“Avoiding obesity and excessive energy supply may help to decrease the risk of leukemia relapse,” said study author Lai Chan, PhD, also of City of Hope.
To test that theory, Drs Chan and Müschen and their colleagues plan to perform experiments in animal models to evaluate the efficacy of dietary restriction on patient-derived childhood leukemia cells, and to assess the activity of drugs that reduce leukemia cells’ glucose and energy supply.
“Based on the outcome of these studies, we plan to introduce dietary restriction and/or glucose-restricting drugs into a clinical trial for children who are at risk to develop leukemia relapse,” Dr Müschen said.