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Immunotherapy shows promise in CBCL
diffuse large B-cell lymphoma
Credit: Leszek Woźniak
& Krzysztof W. Zieliński
An immunotherapeutic agent can confer clinical benefit in patients with relapsed cutaneous B-cell lymphoma (CBCL), results of a small phase 2 study suggest.
The therapy, TG1042, is human adenovirus type 5 engineered to express interferon-gamma.
Repeat injections of TG1042 elicited responses in 11 of 12 evaluable patients, with complete responses in 7.
All 13 of the patients enrolled on the study experienced an adverse event that may have been related to TG1042, but most were grade 1 or 2 in severity.
“Intralesional TG1042 therapy is well-tolerated and results in lasting tumor regressions,” said study author Reinhard Dummer, MD, of the University of Zurich in Switzerland.
He and his colleagues reported these results in PLOS ONE. The study was sponsored by Transgene SA, makers of TG1042.
The trial consisted of 13 patients with primary CBCL, including primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma other than leg type, and T-cell/histiocyte-rich B-cell lymphoma.
Patients were required to have either relapsed or active disease after at least 1 first-line treatment.
The patients received intralesional injections of TG1042 at 5 x 1010 viral particles per lesion. They could receive injections in up to 6 lesions, which were treated simultaneously on days 1, 8, and 15 of a 4-week cycle.
Patients did not receive treatment during the fourth week. At the end of the cycle, the researchers evaluated tumors for response.
If patients’ disease did not progress, they could receive an additional cycle, up to a maximum of 4. If patients responded to treatment and their lesions disappeared, they were eligible to receive a second series of injections in untreated lesions.
Of the 13 patients treated, 12 were evaluable for response. Eleven of the patients (85%) achieved an objective response—7 complete responses and 4 partial responses. One patient had stable disease.
All reviewed skin biopsies showed that lesions improved after treatment, with a decrease of the lymphoid infiltrate.
The median time to first objective response was 3.2 months (rage, 1-17.5 months). Among complete responders, the median time to response was 4.3 months (range, 1.4-17.5 months).
The median time to progression was 23.5 months (range, 6.5-26.4+ months).
All 13 patients were included in the safety evaluation, and all experienced 1 or more adverse events that were considered possibly or probably related to the treatment.
One patient discontinued treatment due to influenza-like illness, pyrexia, headache, and skin blisters that were possibly related to TG1042.
Another patient had grade 3 increased lipase, but this was thought to be unrelated to TG1042. And it resolved without treatment.
All other adverse events were grade 1 or 2 in nature. They included fatigue, headache, pyrexia, chills, influenza-like illness, injection site irritation, injection site erythema, and injection site pain.
All of these reactions resolved after treatment discontinuation. 
diffuse large B-cell lymphoma
Credit: Leszek Woźniak
& Krzysztof W. Zieliński
An immunotherapeutic agent can confer clinical benefit in patients with relapsed cutaneous B-cell lymphoma (CBCL), results of a small phase 2 study suggest.
The therapy, TG1042, is human adenovirus type 5 engineered to express interferon-gamma.
Repeat injections of TG1042 elicited responses in 11 of 12 evaluable patients, with complete responses in 7.
All 13 of the patients enrolled on the study experienced an adverse event that may have been related to TG1042, but most were grade 1 or 2 in severity.
“Intralesional TG1042 therapy is well-tolerated and results in lasting tumor regressions,” said study author Reinhard Dummer, MD, of the University of Zurich in Switzerland.
He and his colleagues reported these results in PLOS ONE. The study was sponsored by Transgene SA, makers of TG1042.
The trial consisted of 13 patients with primary CBCL, including primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma other than leg type, and T-cell/histiocyte-rich B-cell lymphoma.
Patients were required to have either relapsed or active disease after at least 1 first-line treatment.
The patients received intralesional injections of TG1042 at 5 x 1010 viral particles per lesion. They could receive injections in up to 6 lesions, which were treated simultaneously on days 1, 8, and 15 of a 4-week cycle.
Patients did not receive treatment during the fourth week. At the end of the cycle, the researchers evaluated tumors for response.
If patients’ disease did not progress, they could receive an additional cycle, up to a maximum of 4. If patients responded to treatment and their lesions disappeared, they were eligible to receive a second series of injections in untreated lesions.
Of the 13 patients treated, 12 were evaluable for response. Eleven of the patients (85%) achieved an objective response—7 complete responses and 4 partial responses. One patient had stable disease.
All reviewed skin biopsies showed that lesions improved after treatment, with a decrease of the lymphoid infiltrate.
The median time to first objective response was 3.2 months (rage, 1-17.5 months). Among complete responders, the median time to response was 4.3 months (range, 1.4-17.5 months).
The median time to progression was 23.5 months (range, 6.5-26.4+ months).
All 13 patients were included in the safety evaluation, and all experienced 1 or more adverse events that were considered possibly or probably related to the treatment.
One patient discontinued treatment due to influenza-like illness, pyrexia, headache, and skin blisters that were possibly related to TG1042.
Another patient had grade 3 increased lipase, but this was thought to be unrelated to TG1042. And it resolved without treatment.
All other adverse events were grade 1 or 2 in nature. They included fatigue, headache, pyrexia, chills, influenza-like illness, injection site irritation, injection site erythema, and injection site pain.
All of these reactions resolved after treatment discontinuation.
diffuse large B-cell lymphoma
Credit: Leszek Woźniak
& Krzysztof W. Zieliński
An immunotherapeutic agent can confer clinical benefit in patients with relapsed cutaneous B-cell lymphoma (CBCL), results of a small phase 2 study suggest.
The therapy, TG1042, is human adenovirus type 5 engineered to express interferon-gamma.
Repeat injections of TG1042 elicited responses in 11 of 12 evaluable patients, with complete responses in 7.
All 13 of the patients enrolled on the study experienced an adverse event that may have been related to TG1042, but most were grade 1 or 2 in severity.
“Intralesional TG1042 therapy is well-tolerated and results in lasting tumor regressions,” said study author Reinhard Dummer, MD, of the University of Zurich in Switzerland.
He and his colleagues reported these results in PLOS ONE. The study was sponsored by Transgene SA, makers of TG1042.
The trial consisted of 13 patients with primary CBCL, including primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma other than leg type, and T-cell/histiocyte-rich B-cell lymphoma.
Patients were required to have either relapsed or active disease after at least 1 first-line treatment.
The patients received intralesional injections of TG1042 at 5 x 1010 viral particles per lesion. They could receive injections in up to 6 lesions, which were treated simultaneously on days 1, 8, and 15 of a 4-week cycle.
Patients did not receive treatment during the fourth week. At the end of the cycle, the researchers evaluated tumors for response.
If patients’ disease did not progress, they could receive an additional cycle, up to a maximum of 4. If patients responded to treatment and their lesions disappeared, they were eligible to receive a second series of injections in untreated lesions.
Of the 13 patients treated, 12 were evaluable for response. Eleven of the patients (85%) achieved an objective response—7 complete responses and 4 partial responses. One patient had stable disease.
All reviewed skin biopsies showed that lesions improved after treatment, with a decrease of the lymphoid infiltrate.
The median time to first objective response was 3.2 months (rage, 1-17.5 months). Among complete responders, the median time to response was 4.3 months (range, 1.4-17.5 months).
The median time to progression was 23.5 months (range, 6.5-26.4+ months).
All 13 patients were included in the safety evaluation, and all experienced 1 or more adverse events that were considered possibly or probably related to the treatment.
One patient discontinued treatment due to influenza-like illness, pyrexia, headache, and skin blisters that were possibly related to TG1042.
Another patient had grade 3 increased lipase, but this was thought to be unrelated to TG1042. And it resolved without treatment.
All other adverse events were grade 1 or 2 in nature. They included fatigue, headache, pyrexia, chills, influenza-like illness, injection site irritation, injection site erythema, and injection site pain.
All of these reactions resolved after treatment discontinuation.
Endothelial cells seem to support lymphoma growth
Credit: NIH
Researchers have found evidence to suggest that endothelial cells produce proteins that nurture lymphoma, thereby turning a slow-growing malignancy into an aggressive, treatment-resistant disease.
Their findings, published in Cancer Cell, challenge previous theories about cancer growth and development.
The research suggests it is not simply the number of genetic mutations in cancer cells that determines the aggressiveness of the disease.
Rather, lethality occurs when the cancer hijacks the reparative function of blood vessels, a step that ensures tumor cells’ ability to spread and resist treatment.
The researchers also found the crucial nurturing molecules that cancer co-opts from tumor blood vessels to promote invasiveness and resistance to chemotherapy. Experiments in mice showed that shutting down these previously unrecognized biological signals makes lymphoma less aggressive and improves survival.
“The endothelial cells that line the vessels orchestrate a wide variety of biological processes, good and bad,” said study author Shahin Rafii, MD, of Weill Cornell Medical College in New York.
“The understanding and control of blood vessel function and how this changes the malignant behaviors of cancer cells is a transformative concept and will pave the way for designing innovative treatments that disrupt signals from the local environment housing the tumor cells—a strategy that has been unappreciated.”
Dr Rafii and his colleagues studied human B-cell lymphoma cells in vitro and in mice. The team found that although the lymphoma cells harbor the same mutations, it is their interaction with and support from endothelial cells that dictates the fate and features of the disease.
Specifically, when slow-growing tumor cells come into contact with endothelial cells expressing the protein Jagged1 (Jag1), they become more aggressive and resistant to chemotherapy. However, when Jag1 is not available from surrounding blood vessels, the lethal features of the tumor cells are absent.
The researchers also found that when Jag1 binds to and activates the receptor Notch2 on tumor cells, the lymphoma becomes more tolerant of chemotherapy.
“We think signals from these abnormally stimulated tumor endothelial cells modulate the malignant features of lymphoma cells,” said Joseph Scandura, MD, PhD, of Weill Cornell. “This is a reversible process dictated by the location of the tumor cells rather than their genetics.”
“This is a critical finding because it suggests that targeting the endothelial cells with agents that disrupt their specific pro-tumorigenic signals can transform aggressive cancers into slow-growing cancers that are more sensitive to chemotherapy.”
The researchers found, for example, that blocking the Notch2 receptor in lymphoma cells or Jag1 on blood vessels made the lymphoma cells significantly more vulnerable to chemotherapy.
“This new approach to treatment would interfere with the nurturing proteins produced by tumor blood vessels,” said Bi-Sen Ding, PhD, of Weill Cornell. “It is different from traditional anti-angiogenic therapy that aims to eradicate all blood vessels in the tumor and prevent them from bringing oxygen and nutrients to the cancer.”
Dr Ding noted that conventional anti-angiogenic therapy can sometimes increase tumor cell aggressiveness by enhancing the expansion of tumor blood vessels.
But blocking specific proteins produced by the tumor blood vessels, such as Jag1, without altering oxygen and nutrient delivery, can circumvent this problem. And this approach could be translated to the clinical setting.
“[W]e can target tumor blood vessels by delivering biological cruise missiles loaded with inhibitory agents for specific cancer-promoting proteins,” Dr Ding said. This could halt tumor growth and increase sensitivity to chemotherapy.
The researchers also believe this study suggests that screening for anticancer drugs may be more effective if tumor cells are assayed in the context of signals derived from the subverted blood vessels.
Credit: NIH
Researchers have found evidence to suggest that endothelial cells produce proteins that nurture lymphoma, thereby turning a slow-growing malignancy into an aggressive, treatment-resistant disease.
Their findings, published in Cancer Cell, challenge previous theories about cancer growth and development.
The research suggests it is not simply the number of genetic mutations in cancer cells that determines the aggressiveness of the disease.
Rather, lethality occurs when the cancer hijacks the reparative function of blood vessels, a step that ensures tumor cells’ ability to spread and resist treatment.
The researchers also found the crucial nurturing molecules that cancer co-opts from tumor blood vessels to promote invasiveness and resistance to chemotherapy. Experiments in mice showed that shutting down these previously unrecognized biological signals makes lymphoma less aggressive and improves survival.
“The endothelial cells that line the vessels orchestrate a wide variety of biological processes, good and bad,” said study author Shahin Rafii, MD, of Weill Cornell Medical College in New York.
“The understanding and control of blood vessel function and how this changes the malignant behaviors of cancer cells is a transformative concept and will pave the way for designing innovative treatments that disrupt signals from the local environment housing the tumor cells—a strategy that has been unappreciated.”
Dr Rafii and his colleagues studied human B-cell lymphoma cells in vitro and in mice. The team found that although the lymphoma cells harbor the same mutations, it is their interaction with and support from endothelial cells that dictates the fate and features of the disease.
Specifically, when slow-growing tumor cells come into contact with endothelial cells expressing the protein Jagged1 (Jag1), they become more aggressive and resistant to chemotherapy. However, when Jag1 is not available from surrounding blood vessels, the lethal features of the tumor cells are absent.
The researchers also found that when Jag1 binds to and activates the receptor Notch2 on tumor cells, the lymphoma becomes more tolerant of chemotherapy.
“We think signals from these abnormally stimulated tumor endothelial cells modulate the malignant features of lymphoma cells,” said Joseph Scandura, MD, PhD, of Weill Cornell. “This is a reversible process dictated by the location of the tumor cells rather than their genetics.”
“This is a critical finding because it suggests that targeting the endothelial cells with agents that disrupt their specific pro-tumorigenic signals can transform aggressive cancers into slow-growing cancers that are more sensitive to chemotherapy.”
The researchers found, for example, that blocking the Notch2 receptor in lymphoma cells or Jag1 on blood vessels made the lymphoma cells significantly more vulnerable to chemotherapy.
“This new approach to treatment would interfere with the nurturing proteins produced by tumor blood vessels,” said Bi-Sen Ding, PhD, of Weill Cornell. “It is different from traditional anti-angiogenic therapy that aims to eradicate all blood vessels in the tumor and prevent them from bringing oxygen and nutrients to the cancer.”
Dr Ding noted that conventional anti-angiogenic therapy can sometimes increase tumor cell aggressiveness by enhancing the expansion of tumor blood vessels.
But blocking specific proteins produced by the tumor blood vessels, such as Jag1, without altering oxygen and nutrient delivery, can circumvent this problem. And this approach could be translated to the clinical setting.
“[W]e can target tumor blood vessels by delivering biological cruise missiles loaded with inhibitory agents for specific cancer-promoting proteins,” Dr Ding said. This could halt tumor growth and increase sensitivity to chemotherapy.
The researchers also believe this study suggests that screening for anticancer drugs may be more effective if tumor cells are assayed in the context of signals derived from the subverted blood vessels.
Credit: NIH
Researchers have found evidence to suggest that endothelial cells produce proteins that nurture lymphoma, thereby turning a slow-growing malignancy into an aggressive, treatment-resistant disease.
Their findings, published in Cancer Cell, challenge previous theories about cancer growth and development.
The research suggests it is not simply the number of genetic mutations in cancer cells that determines the aggressiveness of the disease.
Rather, lethality occurs when the cancer hijacks the reparative function of blood vessels, a step that ensures tumor cells’ ability to spread and resist treatment.
The researchers also found the crucial nurturing molecules that cancer co-opts from tumor blood vessels to promote invasiveness and resistance to chemotherapy. Experiments in mice showed that shutting down these previously unrecognized biological signals makes lymphoma less aggressive and improves survival.
“The endothelial cells that line the vessels orchestrate a wide variety of biological processes, good and bad,” said study author Shahin Rafii, MD, of Weill Cornell Medical College in New York.
“The understanding and control of blood vessel function and how this changes the malignant behaviors of cancer cells is a transformative concept and will pave the way for designing innovative treatments that disrupt signals from the local environment housing the tumor cells—a strategy that has been unappreciated.”
Dr Rafii and his colleagues studied human B-cell lymphoma cells in vitro and in mice. The team found that although the lymphoma cells harbor the same mutations, it is their interaction with and support from endothelial cells that dictates the fate and features of the disease.
Specifically, when slow-growing tumor cells come into contact with endothelial cells expressing the protein Jagged1 (Jag1), they become more aggressive and resistant to chemotherapy. However, when Jag1 is not available from surrounding blood vessels, the lethal features of the tumor cells are absent.
The researchers also found that when Jag1 binds to and activates the receptor Notch2 on tumor cells, the lymphoma becomes more tolerant of chemotherapy.
“We think signals from these abnormally stimulated tumor endothelial cells modulate the malignant features of lymphoma cells,” said Joseph Scandura, MD, PhD, of Weill Cornell. “This is a reversible process dictated by the location of the tumor cells rather than their genetics.”
“This is a critical finding because it suggests that targeting the endothelial cells with agents that disrupt their specific pro-tumorigenic signals can transform aggressive cancers into slow-growing cancers that are more sensitive to chemotherapy.”
The researchers found, for example, that blocking the Notch2 receptor in lymphoma cells or Jag1 on blood vessels made the lymphoma cells significantly more vulnerable to chemotherapy.
“This new approach to treatment would interfere with the nurturing proteins produced by tumor blood vessels,” said Bi-Sen Ding, PhD, of Weill Cornell. “It is different from traditional anti-angiogenic therapy that aims to eradicate all blood vessels in the tumor and prevent them from bringing oxygen and nutrients to the cancer.”
Dr Ding noted that conventional anti-angiogenic therapy can sometimes increase tumor cell aggressiveness by enhancing the expansion of tumor blood vessels.
But blocking specific proteins produced by the tumor blood vessels, such as Jag1, without altering oxygen and nutrient delivery, can circumvent this problem. And this approach could be translated to the clinical setting.
“[W]e can target tumor blood vessels by delivering biological cruise missiles loaded with inhibitory agents for specific cancer-promoting proteins,” Dr Ding said. This could halt tumor growth and increase sensitivity to chemotherapy.
The researchers also believe this study suggests that screening for anticancer drugs may be more effective if tumor cells are assayed in the context of signals derived from the subverted blood vessels.
Anticancer drugs might promote lymphoma
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.
Omitting RT can increase risk of relapse in HL
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Credit: Sue Campbell
Interim results of a randomized trial suggest that omitting radiotherapy in Hodgkin lymphoma patients with an early negative PET scan can increase their risk of relapse.
Patients with stage I/II Hodgkin lymphoma who received involved-node radiotherapy after chemotherapy with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazin) were less likely to relapse than patients who received ABVD alone, regardless of prognosis.
However, patients who received chemotherapy alone still had a high rate of progression-free survival (PFS), at about 95%.
John M.M. Raemaekers, MD, PhD, of the Radboud University Medical Center in Nijmegen, The Netherlands, and his colleagues reported these results in the Journal of Clinical Oncology.
“Striking the right balance between initial cure through combined-modality treatment and accepting a higher risk of late complications, and a higher recurrence rate after omitting radiotherapy in subsets of patients who will subsequently need intensive salvage treatment, is a matter of unsettled debate,” Dr Raemaekers said.
So he and his colleagues set out to evaluate whether involved-node radiotherapy could be omitted without compromising PFS in patients with stage I/II Hodgkin lymphoma who had an early negative PET scan after treatment with ABVD.
The interim analysis included 1137 patients with untreated clinical stage I/II Hodgkin lymphoma. Of these, 444 patients had favorable prognoses, and 693 had unfavorable prognoses.
Patients in each prognostic group were randomized to receive standard treatment—2 cycles of ABVD followed by radiotherapy (n=188)—or experimental treatment—ABVD alone (n=193).
For patients with a favorable prognosis and an early negative PET scan, 1 progression occurred in the standard arm, and 9 occurred in the experimental arm. At 1 year, PFS rates were 100% and 94.9%, respectively.
For patients with unfavorable prognosis and an early negative PET scan, 7 events occurred in the standard arm, and 16 occurred in the experimental arm.
One patient died from toxicity without signs of progression, but all of the remaining events were progressions. At 1 year, the PFS rates were 97.3% and 94.7%, respectively.
Although there were few events and the median follow-up time was short, an independent data monitoring committee said it was unlikely that the final results would show non-inferiority for the experimental treatment. They therefore advised that randomization be stopped for early PET-negative patients.
Cancer survivors’ risk of health problems increases with age
cancer patient and her father
Credit: Rhoda Baer
The “health gap” between childhood cancer survivors and their siblings widens with age, according to a study published in the Journal of Clinical Oncology.
Cancer survivors aged 20 to 34 years old were 3.8 times more likely than siblings of the same age to develop new cancers and other serious health conditions.
By age 35 and beyond, survivors had a 5-fold greater risk.
“Survivors remain at risk for serious health problems into their 40s and 50s, decades after they have completed treatment for childhood cancer,” said study author Gregory Armstrong, MD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.
“In fact, for survivors, the risk of illness and death increases significantly beyond the age of 35. Their siblings don’t share these same risks.”
Dr Armstrong and his colleagues uncovered these results by analyzing data from the Childhood Cancer Survivor Study, which included 14,359 survivors and 4301 healthy siblings.
The patients had been diagnosed with leukemias, lymphomas, and other pediatric cancers before age 21 and were followed for a median of 24.5 years (range, 5 to 39.3 years).
The researchers compared survivors to age-matched siblings, evaluating the incidence of severe, disabling, life-threatening, or fatal health conditions. This included new malignancies as well as diseases of the heart, lungs, liver, kidneys, and hormones.
The team found a heightened risk of these health conditions among cancer survivors. And that risk increased as the survivors aged.
At 20 years of age, 16% of survivors had serious health conditions, compared to 3.3% of siblings. But by age 50, the incidence had increased to 53.6% among survivors and 19.8% among siblings. At 50, 22.5% of survivors had at least 2 serious health problems, and 10.1% had 3 or more.
In a multivariate analysis, the hazard ratio for developing serious health conditions was significantly higher among survivors aged 35 and older than for those aged 20 to 34 (P=0.03).
Among survivors who reached age 35 without serious health problems, 25.9% developed a significant health problem in the next decade. In comparison, 6% of siblings developed their first serious health condition between the ages of 35 and 45.
In addition to showing a health gap between childhood cancer survivors and their siblings, this research adds to evidence that survivors experience accelerated aging. The 24-year-old cancer survivors had roughly the same cumulative incidence of grade 3 to 5 health conditions (19.6%) as the 50-year-old siblings (19.8%).
Overall, these findings highlight the importance of lifelong, risk-based healthcare for childhood cancer survivors, Dr Armstrong said. Depending on their cancer treatment and other risk factors, follow-up care may include performing health checks at a younger age than is recommended for the general public.
This study involved survivors whose cancer was diagnosed between 1970 and 1986. The researchers are now studying the health of adult cancer survivors from a more recent treatment era.
cancer patient and her father
Credit: Rhoda Baer
The “health gap” between childhood cancer survivors and their siblings widens with age, according to a study published in the Journal of Clinical Oncology.
Cancer survivors aged 20 to 34 years old were 3.8 times more likely than siblings of the same age to develop new cancers and other serious health conditions.
By age 35 and beyond, survivors had a 5-fold greater risk.
“Survivors remain at risk for serious health problems into their 40s and 50s, decades after they have completed treatment for childhood cancer,” said study author Gregory Armstrong, MD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.
“In fact, for survivors, the risk of illness and death increases significantly beyond the age of 35. Their siblings don’t share these same risks.”
Dr Armstrong and his colleagues uncovered these results by analyzing data from the Childhood Cancer Survivor Study, which included 14,359 survivors and 4301 healthy siblings.
The patients had been diagnosed with leukemias, lymphomas, and other pediatric cancers before age 21 and were followed for a median of 24.5 years (range, 5 to 39.3 years).
The researchers compared survivors to age-matched siblings, evaluating the incidence of severe, disabling, life-threatening, or fatal health conditions. This included new malignancies as well as diseases of the heart, lungs, liver, kidneys, and hormones.
The team found a heightened risk of these health conditions among cancer survivors. And that risk increased as the survivors aged.
At 20 years of age, 16% of survivors had serious health conditions, compared to 3.3% of siblings. But by age 50, the incidence had increased to 53.6% among survivors and 19.8% among siblings. At 50, 22.5% of survivors had at least 2 serious health problems, and 10.1% had 3 or more.
In a multivariate analysis, the hazard ratio for developing serious health conditions was significantly higher among survivors aged 35 and older than for those aged 20 to 34 (P=0.03).
Among survivors who reached age 35 without serious health problems, 25.9% developed a significant health problem in the next decade. In comparison, 6% of siblings developed their first serious health condition between the ages of 35 and 45.
In addition to showing a health gap between childhood cancer survivors and their siblings, this research adds to evidence that survivors experience accelerated aging. The 24-year-old cancer survivors had roughly the same cumulative incidence of grade 3 to 5 health conditions (19.6%) as the 50-year-old siblings (19.8%).
Overall, these findings highlight the importance of lifelong, risk-based healthcare for childhood cancer survivors, Dr Armstrong said. Depending on their cancer treatment and other risk factors, follow-up care may include performing health checks at a younger age than is recommended for the general public.
This study involved survivors whose cancer was diagnosed between 1970 and 1986. The researchers are now studying the health of adult cancer survivors from a more recent treatment era.
cancer patient and her father
Credit: Rhoda Baer
The “health gap” between childhood cancer survivors and their siblings widens with age, according to a study published in the Journal of Clinical Oncology.
Cancer survivors aged 20 to 34 years old were 3.8 times more likely than siblings of the same age to develop new cancers and other serious health conditions.
By age 35 and beyond, survivors had a 5-fold greater risk.
“Survivors remain at risk for serious health problems into their 40s and 50s, decades after they have completed treatment for childhood cancer,” said study author Gregory Armstrong, MD, of the St Jude Children’s Research Hospital in Memphis, Tennessee.
“In fact, for survivors, the risk of illness and death increases significantly beyond the age of 35. Their siblings don’t share these same risks.”
Dr Armstrong and his colleagues uncovered these results by analyzing data from the Childhood Cancer Survivor Study, which included 14,359 survivors and 4301 healthy siblings.
The patients had been diagnosed with leukemias, lymphomas, and other pediatric cancers before age 21 and were followed for a median of 24.5 years (range, 5 to 39.3 years).
The researchers compared survivors to age-matched siblings, evaluating the incidence of severe, disabling, life-threatening, or fatal health conditions. This included new malignancies as well as diseases of the heart, lungs, liver, kidneys, and hormones.
The team found a heightened risk of these health conditions among cancer survivors. And that risk increased as the survivors aged.
At 20 years of age, 16% of survivors had serious health conditions, compared to 3.3% of siblings. But by age 50, the incidence had increased to 53.6% among survivors and 19.8% among siblings. At 50, 22.5% of survivors had at least 2 serious health problems, and 10.1% had 3 or more.
In a multivariate analysis, the hazard ratio for developing serious health conditions was significantly higher among survivors aged 35 and older than for those aged 20 to 34 (P=0.03).
Among survivors who reached age 35 without serious health problems, 25.9% developed a significant health problem in the next decade. In comparison, 6% of siblings developed their first serious health condition between the ages of 35 and 45.
In addition to showing a health gap between childhood cancer survivors and their siblings, this research adds to evidence that survivors experience accelerated aging. The 24-year-old cancer survivors had roughly the same cumulative incidence of grade 3 to 5 health conditions (19.6%) as the 50-year-old siblings (19.8%).
Overall, these findings highlight the importance of lifelong, risk-based healthcare for childhood cancer survivors, Dr Armstrong said. Depending on their cancer treatment and other risk factors, follow-up care may include performing health checks at a younger age than is recommended for the general public.
This study involved survivors whose cancer was diagnosed between 1970 and 1986. The researchers are now studying the health of adult cancer survivors from a more recent treatment era.
Adult minorities underrepresented in cancer trials
Credit: Rhoda Baer
New research indicates that less than 2% of trials funded by the National Cancer Institute focus on racial and ethnic minorities, and minority participation in adult cancer trials is not representative of the US population.
The researchers said these findings suggest we must do more to promote minority-focused research and clinical trial recruitment, beyond the National Institutes of Health (NIH) Revitalization Act of 1993, which mandated the appropriate inclusion of minorities in all NIH-funded research.
“What is needed is deliberate effort,” said study author Moon Chen, Jr, PhD, of the University of California, Davis. “Minorities are not hard to reach. They are hardly reached.”
To assess minority inclusion in clinical trials, Dr Chen and his colleagues searched ClinicalTrials.gov, looking for trials sponsored by the National Cancer Institute that were available in January 2013.
They searched using terms for different minority groups, then counted the number of clinical trials with a primary focus on a particular ethnic or minority population. Roughly 150 trials out of 10,000—or less than 2%—met the criteria.
The researchers also reviewed abstracts and articles accessed from January through March 2013 on PubMed to find those that specifically examined minority accrual in clinical trials.
Of the 42 citations found, 5 included reports explicitly discussing participation levels by race and ethnicity. Those reports revealed an “encouraging but less than optimal” increase in specification of race or ethnicity in published results of clinical trials.
Dr Chen and his colleagues also reported that participation of adult minorities is not proportional to their representation in the US population.
For example, African Americans experience the highest cancer incidence of any racial group (593.7 cases per 100,000), but they have the lowest rates of cancer trial participation (tied with Hispanics), at 1.3%. It’s important to note, however, that clinical trial participation is low for all adult cancer patients, at 3% to 5%.
In contrast, the researchers pointed out that 60% of all patients under age 15 are enrolled in clinical trials. And minority representation among children is excellent, either equal to or greater than their proportion of the population.
To put the adult population on par with the pediatric population, researchers should design trials to include and focus on specific populations, Dr Chen said. Furthermore, scientific journals should insist on appropriate representation and analyses of NIH research by race and ethnicity.
“Whatever happens in the laboratory or in the clinic needs to be applied to solving real-world problems,” Dr Chen said. “And those relate to the disproportionate effects of cancer and other diseases on racial and ethnic minorities.”
Dr Chen and his colleagues reported this research in Cancer.
Credit: Rhoda Baer
New research indicates that less than 2% of trials funded by the National Cancer Institute focus on racial and ethnic minorities, and minority participation in adult cancer trials is not representative of the US population.
The researchers said these findings suggest we must do more to promote minority-focused research and clinical trial recruitment, beyond the National Institutes of Health (NIH) Revitalization Act of 1993, which mandated the appropriate inclusion of minorities in all NIH-funded research.
“What is needed is deliberate effort,” said study author Moon Chen, Jr, PhD, of the University of California, Davis. “Minorities are not hard to reach. They are hardly reached.”
To assess minority inclusion in clinical trials, Dr Chen and his colleagues searched ClinicalTrials.gov, looking for trials sponsored by the National Cancer Institute that were available in January 2013.
They searched using terms for different minority groups, then counted the number of clinical trials with a primary focus on a particular ethnic or minority population. Roughly 150 trials out of 10,000—or less than 2%—met the criteria.
The researchers also reviewed abstracts and articles accessed from January through March 2013 on PubMed to find those that specifically examined minority accrual in clinical trials.
Of the 42 citations found, 5 included reports explicitly discussing participation levels by race and ethnicity. Those reports revealed an “encouraging but less than optimal” increase in specification of race or ethnicity in published results of clinical trials.
Dr Chen and his colleagues also reported that participation of adult minorities is not proportional to their representation in the US population.
For example, African Americans experience the highest cancer incidence of any racial group (593.7 cases per 100,000), but they have the lowest rates of cancer trial participation (tied with Hispanics), at 1.3%. It’s important to note, however, that clinical trial participation is low for all adult cancer patients, at 3% to 5%.
In contrast, the researchers pointed out that 60% of all patients under age 15 are enrolled in clinical trials. And minority representation among children is excellent, either equal to or greater than their proportion of the population.
To put the adult population on par with the pediatric population, researchers should design trials to include and focus on specific populations, Dr Chen said. Furthermore, scientific journals should insist on appropriate representation and analyses of NIH research by race and ethnicity.
“Whatever happens in the laboratory or in the clinic needs to be applied to solving real-world problems,” Dr Chen said. “And those relate to the disproportionate effects of cancer and other diseases on racial and ethnic minorities.”
Dr Chen and his colleagues reported this research in Cancer.
Credit: Rhoda Baer
New research indicates that less than 2% of trials funded by the National Cancer Institute focus on racial and ethnic minorities, and minority participation in adult cancer trials is not representative of the US population.
The researchers said these findings suggest we must do more to promote minority-focused research and clinical trial recruitment, beyond the National Institutes of Health (NIH) Revitalization Act of 1993, which mandated the appropriate inclusion of minorities in all NIH-funded research.
“What is needed is deliberate effort,” said study author Moon Chen, Jr, PhD, of the University of California, Davis. “Minorities are not hard to reach. They are hardly reached.”
To assess minority inclusion in clinical trials, Dr Chen and his colleagues searched ClinicalTrials.gov, looking for trials sponsored by the National Cancer Institute that were available in January 2013.
They searched using terms for different minority groups, then counted the number of clinical trials with a primary focus on a particular ethnic or minority population. Roughly 150 trials out of 10,000—or less than 2%—met the criteria.
The researchers also reviewed abstracts and articles accessed from January through March 2013 on PubMed to find those that specifically examined minority accrual in clinical trials.
Of the 42 citations found, 5 included reports explicitly discussing participation levels by race and ethnicity. Those reports revealed an “encouraging but less than optimal” increase in specification of race or ethnicity in published results of clinical trials.
Dr Chen and his colleagues also reported that participation of adult minorities is not proportional to their representation in the US population.
For example, African Americans experience the highest cancer incidence of any racial group (593.7 cases per 100,000), but they have the lowest rates of cancer trial participation (tied with Hispanics), at 1.3%. It’s important to note, however, that clinical trial participation is low for all adult cancer patients, at 3% to 5%.
In contrast, the researchers pointed out that 60% of all patients under age 15 are enrolled in clinical trials. And minority representation among children is excellent, either equal to or greater than their proportion of the population.
To put the adult population on par with the pediatric population, researchers should design trials to include and focus on specific populations, Dr Chen said. Furthermore, scientific journals should insist on appropriate representation and analyses of NIH research by race and ethnicity.
“Whatever happens in the laboratory or in the clinic needs to be applied to solving real-world problems,” Dr Chen said. “And those relate to the disproportionate effects of cancer and other diseases on racial and ethnic minorities.”
Dr Chen and his colleagues reported this research in Cancer.
Electronics workers may have elevated risk of death from NHL
Researchers have found evidence suggesting that men who work in microelectronics and business machine facilities may have an increased risk of dying from certain cancers, including non-Hodgkin lymphoma (NHL).
Their study, published in the American Journal of Industrial Medicine, was designed to assess the effects chemical exposure might have on the incidence of diseases and worker mortality.
The results showed that hourly male workers, who were more likely than other employees to be exposed to the chemicals studied, had a 1.5-fold increased risk of death from NHL.
However, the investigators did not observe a significant relationship between NHL and any of the chemicals studied.
This research originated from concerns about the release of trichloroethylene (TCE), perchlorethylene (PCE), and other industrial chemicals through groundwater and air emissions from several industrial facilities in a town in upstate New York.
Previous studies suggested the chemicals were associated with increases in the incidence of kidney, lung, and testicular cancer in the community. So researchers initiated a study of current and former workers of the local microelectronics and business machine facility.
Patient population
Sharon R. Silver, of the National Institute for Occupational Safety and Health in Cincinnati, Ohio, and her colleagues examined health outcomes among 34,494 former workers employed at the facility for at least 91 days between 1969 and 2001.
Machining workers were exposed to dust, noise, solvents, and metals. And “wet” process workers were exposed to chemical solutions used in manufacturing circuit boards and their substrates. The facility also had employees in non-production roles, including sales and office support, as well as computer programming.
The researchers evaluated the relationship between health outcomes and the estimated cumulative extent of potential chemical exposures, stratified according to gender and pay code.
Of the 34,494 workers, 69.7% were male. Among males, 15,447 were hourly workers, and 8590 were salaried. Among females, 8934 were hourly workers, and 1523 were salaried.
Chemical exposure
A previous study of this population revealed the use of 6 chemical agents (fiberglass, lead, methylene chloride, methyl chloroform, PCE, and TCE), 6 chemical classes (acid-base, aromatic hydrocarbons, chlorinated hydrocarbons, other hydrocarbons, chlorofluorocarbons, and metals), and general chemicals (including unspecified).
The potential for exposure to a chemical agent or class was much more common among hourly workers than salaried workers. Among males, 65.7% of hourly workers and 20% of salaried workers were exposed to at least 1 of the chemicals studied. Among females, exposure rates were 58.5% and 13.9%, respectively.
“Other hydrocarbons” was the chemical class that male hourly workers were potentially exposed to most often (60.5%). At least one-third of workers in this group had potential exposure to chlorinated hydrocarbons, lead, and acids and bases. TCE and PCE were the least common exposure agents among male hourly workers, with 13.9% and 15.1% exposed, respectively.
Cancer mortality, incidence
The investigators used mortality rates from the US population, as well as New York State (excluding New York City), to calculate the number of expected deaths among study participants. The standardized mortality ratio (SMR) is the ratio of observed to expected deaths.
The average follow-up was 25.7 years. By the study end date, 5966 workers (17.3%) had died. Workers employed less than a year at the facility (n=8397) comprised 363 of these deaths.
Both all-cause mortality (SMR=0.67) and all-cancer mortality (SMR=0.74) showed a statistically significant deficit for the entire workforce. Most of the individual cancers and other conditions studied were not associated with an increased risk of death.
There were significant increases in death for certain cancers among males, but there was no significant increase in a specific cause of death among females belonging to either pay code.
There was an increased risk of death from NHL among male hourly workers but not salaried workers, with SMRs of 1.49 and 0.68, respectively. The same pattern occurred for rectal cancer, with SMRs of 1.71 and 0.71, respectively.
The study also revealed an elevated incidence of pleural cancers in salaried males, mesothelioma in hourly workers, and testicular cancer in salaried males.
The increase in mesothelioma and pleural cancers was seen only in workers hired before 1969, which would support a link between the cancers and asbestos exposure. However, the researchers could find no evidence that asbestos was used in manufacturing at the facility.
Similarly, the investigators found no significant link between exposure to specific chemicals and the increased mortality from NHL or rectal cancer. And there was no significant link between exposure and testicular cancer.
Although these results do not suggest a strong role for occupational chemical exposures in cancer incidence and mortality, the researchers said risks from occupational exposures cannot be ruled out due to limitations of this study and the relative youth of this patient cohort.
Researchers have found evidence suggesting that men who work in microelectronics and business machine facilities may have an increased risk of dying from certain cancers, including non-Hodgkin lymphoma (NHL).
Their study, published in the American Journal of Industrial Medicine, was designed to assess the effects chemical exposure might have on the incidence of diseases and worker mortality.
The results showed that hourly male workers, who were more likely than other employees to be exposed to the chemicals studied, had a 1.5-fold increased risk of death from NHL.
However, the investigators did not observe a significant relationship between NHL and any of the chemicals studied.
This research originated from concerns about the release of trichloroethylene (TCE), perchlorethylene (PCE), and other industrial chemicals through groundwater and air emissions from several industrial facilities in a town in upstate New York.
Previous studies suggested the chemicals were associated with increases in the incidence of kidney, lung, and testicular cancer in the community. So researchers initiated a study of current and former workers of the local microelectronics and business machine facility.
Patient population
Sharon R. Silver, of the National Institute for Occupational Safety and Health in Cincinnati, Ohio, and her colleagues examined health outcomes among 34,494 former workers employed at the facility for at least 91 days between 1969 and 2001.
Machining workers were exposed to dust, noise, solvents, and metals. And “wet” process workers were exposed to chemical solutions used in manufacturing circuit boards and their substrates. The facility also had employees in non-production roles, including sales and office support, as well as computer programming.
The researchers evaluated the relationship between health outcomes and the estimated cumulative extent of potential chemical exposures, stratified according to gender and pay code.
Of the 34,494 workers, 69.7% were male. Among males, 15,447 were hourly workers, and 8590 were salaried. Among females, 8934 were hourly workers, and 1523 were salaried.
Chemical exposure
A previous study of this population revealed the use of 6 chemical agents (fiberglass, lead, methylene chloride, methyl chloroform, PCE, and TCE), 6 chemical classes (acid-base, aromatic hydrocarbons, chlorinated hydrocarbons, other hydrocarbons, chlorofluorocarbons, and metals), and general chemicals (including unspecified).
The potential for exposure to a chemical agent or class was much more common among hourly workers than salaried workers. Among males, 65.7% of hourly workers and 20% of salaried workers were exposed to at least 1 of the chemicals studied. Among females, exposure rates were 58.5% and 13.9%, respectively.
“Other hydrocarbons” was the chemical class that male hourly workers were potentially exposed to most often (60.5%). At least one-third of workers in this group had potential exposure to chlorinated hydrocarbons, lead, and acids and bases. TCE and PCE were the least common exposure agents among male hourly workers, with 13.9% and 15.1% exposed, respectively.
Cancer mortality, incidence
The investigators used mortality rates from the US population, as well as New York State (excluding New York City), to calculate the number of expected deaths among study participants. The standardized mortality ratio (SMR) is the ratio of observed to expected deaths.
The average follow-up was 25.7 years. By the study end date, 5966 workers (17.3%) had died. Workers employed less than a year at the facility (n=8397) comprised 363 of these deaths.
Both all-cause mortality (SMR=0.67) and all-cancer mortality (SMR=0.74) showed a statistically significant deficit for the entire workforce. Most of the individual cancers and other conditions studied were not associated with an increased risk of death.
There were significant increases in death for certain cancers among males, but there was no significant increase in a specific cause of death among females belonging to either pay code.
There was an increased risk of death from NHL among male hourly workers but not salaried workers, with SMRs of 1.49 and 0.68, respectively. The same pattern occurred for rectal cancer, with SMRs of 1.71 and 0.71, respectively.
The study also revealed an elevated incidence of pleural cancers in salaried males, mesothelioma in hourly workers, and testicular cancer in salaried males.
The increase in mesothelioma and pleural cancers was seen only in workers hired before 1969, which would support a link between the cancers and asbestos exposure. However, the researchers could find no evidence that asbestos was used in manufacturing at the facility.
Similarly, the investigators found no significant link between exposure to specific chemicals and the increased mortality from NHL or rectal cancer. And there was no significant link between exposure and testicular cancer.
Although these results do not suggest a strong role for occupational chemical exposures in cancer incidence and mortality, the researchers said risks from occupational exposures cannot be ruled out due to limitations of this study and the relative youth of this patient cohort.
Researchers have found evidence suggesting that men who work in microelectronics and business machine facilities may have an increased risk of dying from certain cancers, including non-Hodgkin lymphoma (NHL).
Their study, published in the American Journal of Industrial Medicine, was designed to assess the effects chemical exposure might have on the incidence of diseases and worker mortality.
The results showed that hourly male workers, who were more likely than other employees to be exposed to the chemicals studied, had a 1.5-fold increased risk of death from NHL.
However, the investigators did not observe a significant relationship between NHL and any of the chemicals studied.
This research originated from concerns about the release of trichloroethylene (TCE), perchlorethylene (PCE), and other industrial chemicals through groundwater and air emissions from several industrial facilities in a town in upstate New York.
Previous studies suggested the chemicals were associated with increases in the incidence of kidney, lung, and testicular cancer in the community. So researchers initiated a study of current and former workers of the local microelectronics and business machine facility.
Patient population
Sharon R. Silver, of the National Institute for Occupational Safety and Health in Cincinnati, Ohio, and her colleagues examined health outcomes among 34,494 former workers employed at the facility for at least 91 days between 1969 and 2001.
Machining workers were exposed to dust, noise, solvents, and metals. And “wet” process workers were exposed to chemical solutions used in manufacturing circuit boards and their substrates. The facility also had employees in non-production roles, including sales and office support, as well as computer programming.
The researchers evaluated the relationship between health outcomes and the estimated cumulative extent of potential chemical exposures, stratified according to gender and pay code.
Of the 34,494 workers, 69.7% were male. Among males, 15,447 were hourly workers, and 8590 were salaried. Among females, 8934 were hourly workers, and 1523 were salaried.
Chemical exposure
A previous study of this population revealed the use of 6 chemical agents (fiberglass, lead, methylene chloride, methyl chloroform, PCE, and TCE), 6 chemical classes (acid-base, aromatic hydrocarbons, chlorinated hydrocarbons, other hydrocarbons, chlorofluorocarbons, and metals), and general chemicals (including unspecified).
The potential for exposure to a chemical agent or class was much more common among hourly workers than salaried workers. Among males, 65.7% of hourly workers and 20% of salaried workers were exposed to at least 1 of the chemicals studied. Among females, exposure rates were 58.5% and 13.9%, respectively.
“Other hydrocarbons” was the chemical class that male hourly workers were potentially exposed to most often (60.5%). At least one-third of workers in this group had potential exposure to chlorinated hydrocarbons, lead, and acids and bases. TCE and PCE were the least common exposure agents among male hourly workers, with 13.9% and 15.1% exposed, respectively.
Cancer mortality, incidence
The investigators used mortality rates from the US population, as well as New York State (excluding New York City), to calculate the number of expected deaths among study participants. The standardized mortality ratio (SMR) is the ratio of observed to expected deaths.
The average follow-up was 25.7 years. By the study end date, 5966 workers (17.3%) had died. Workers employed less than a year at the facility (n=8397) comprised 363 of these deaths.
Both all-cause mortality (SMR=0.67) and all-cancer mortality (SMR=0.74) showed a statistically significant deficit for the entire workforce. Most of the individual cancers and other conditions studied were not associated with an increased risk of death.
There were significant increases in death for certain cancers among males, but there was no significant increase in a specific cause of death among females belonging to either pay code.
There was an increased risk of death from NHL among male hourly workers but not salaried workers, with SMRs of 1.49 and 0.68, respectively. The same pattern occurred for rectal cancer, with SMRs of 1.71 and 0.71, respectively.
The study also revealed an elevated incidence of pleural cancers in salaried males, mesothelioma in hourly workers, and testicular cancer in salaried males.
The increase in mesothelioma and pleural cancers was seen only in workers hired before 1969, which would support a link between the cancers and asbestos exposure. However, the researchers could find no evidence that asbestos was used in manufacturing at the facility.
Similarly, the investigators found no significant link between exposure to specific chemicals and the increased mortality from NHL or rectal cancer. And there was no significant link between exposure and testicular cancer.
Although these results do not suggest a strong role for occupational chemical exposures in cancer incidence and mortality, the researchers said risks from occupational exposures cannot be ruled out due to limitations of this study and the relative youth of this patient cohort.
FDA approves IV formulation of antifungal agent
The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.
The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.
In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.
This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.
Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.
Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.
Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).
Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).
Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.
Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.
Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.
For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.
The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.
The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.
In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.
This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.
Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.
Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.
Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).
Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).
Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.
Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.
Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.
For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.
The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.
The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.
In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.
This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.
Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.
Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.
Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).
Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).
Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.
Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.
Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.
For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.
How diabetes drugs can fight hematologic malignancies
Credit: PNAS
Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.
The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.
By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.
And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.
Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.
To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.
Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.
Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.
However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.
“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.
To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.
The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.
If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.
The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).
They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.
The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).
“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.
“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”
To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.
Credit: PNAS
Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.
The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.
By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.
And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.
Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.
To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.
Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.
Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.
However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.
“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.
To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.
The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.
If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.
The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).
They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.
The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).
“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.
“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”
To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.
Credit: PNAS
Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.
The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.
By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.
And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.
Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.
To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.
Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.
Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.
However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.
“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.
To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.
The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.
If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.
The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).
They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.
The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).
“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.
“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”
To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.
Mutations appear to drive lymphoma development
Credit: Rhoda Baer
Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.
Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.
And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.
“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.
To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.
As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.
Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.
In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.
The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.
Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.
The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.
Credit: Rhoda Baer
Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.
Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.
And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.
“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.
To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.
As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.
Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.
In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.
The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.
Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.
The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.
Credit: Rhoda Baer
Mutations in the gene PTPN1 may drive the development of Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL), according to a study published in Nature Genetics.
Whole-genome and whole-transcriptome sequencing revealed recurrent PTPN1 mutations in samples and cell lines of HL and PMBCL.
And experiments suggested the mutations contribute to lymphomagenesis by activating JAK-STAT signaling pathways.
“Our work identifies, for the first time, the entirety of genetic mutations in primary mediastinal B-cell lymphoma and first-of-its kind-mutations in the PTPN1 gene,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver.
To discover these mutations, Dr Steidl and his colleagues sequenced samples from 77 PMBCL patients and 3 PMBCL-derived cell lines. The team found mutations in 2 negative regulators of the JAK-STAT signaling pathway—SOCS1 and PTPN1.
As SOCS1 is already well-characterized, the researchers decided to focus on PTPN1. They identified PTPN1 mutations in 22% (17/77) of PMBCL cases and 33% (1/3) of the PMBCL-derived cell lines.
Because classical HL is closely related to PMBCL, the investigators also screened 30 samples from HL patients and 9 HL-derived cell lines. PTPN1 mutations were present in 20% (6/30) of the samples and 67% (6/9) of the cell lines.
In all, the team identified 18 (60%) missense mutations, 4 (13.3%) frameshift mutations, 3 (10%) single-amino acid deletions, 4 (13.3%) nonsense mutations, and 1 (3.3%) promoter mutation.
The researchers also discovered that PTPN1 mutations were significantly associated with diminished PTP1B expression in patient samples. However, they said future studies will need to confirm whether PTP1B immunohistochemistry can be used as a surrogate for PTPN1 mutations.
Another key finding was that PTPN1 mutations led to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
When the investigators silenced PTPN1 in the HL cell line KM-H2, they observed hyperphosphorylation and overexpression of downstream oncogenic targets—STAT3, STAT5, STAT6, JAK1, JAK2, and AKT.
The researchers said these results suggest PTPN1 mutations drive lymphomagenesis. The mutations likely synergize with other driver mutations known to be involved in the pathogenesis of HL and PMBCL—such as SOCS1 and STAT6—and that contribute to aberrant JAK-STAT signaling.