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Frequent BCCs linked to blood cancers
New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.
“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.
“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”
Dr Sarin and her colleagues reported their findings in JCI Insight.
Stanford cohort
The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.
“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”
Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.
Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.
When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).
The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).
Insurance cohort
To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.
The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.
The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.
The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.
The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.
The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.
The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.
The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.
“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”
The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.
The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.
New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.
“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.
“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”
Dr Sarin and her colleagues reported their findings in JCI Insight.
Stanford cohort
The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.
“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”
Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.
Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.
When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).
The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).
Insurance cohort
To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.
The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.
The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.
The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.
The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.
The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.
The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.
The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.
“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”
The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.
The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.
New research suggests people who develop frequent cases of basal cell carcinoma (BCC) have an increased risk of leukemias, lymphomas, and other cancers.
“We discovered that people who develop 6 or more basal cell carcinomas during a 10-year period are about 3 times more likely than the general population to develop other, unrelated cancers,” said Kavita Sarin, MD, PhD, of Stanford University School of Medicine in California.
“We’re hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop.”
Dr Sarin and her colleagues reported their findings in JCI Insight.
Stanford cohort
The researchers first studied 61 patients treated at Stanford Health Care for unusually frequent BCCs—an average of 11 per patient over a 10-year period. The team investigated whether these patients may have mutations in 29 genes that code for DNA damage repair proteins.
“We found that about 20% of the people with frequent basal cell carcinomas have a mutation in one of the genes responsible for repairing DNA damage, versus about 3% of the general population,” Dr Sarin said. “That’s shockingly high.”
Specifically, there were 12 BCC patients (19.7%) who had 13 pathogenic mutations in 12 genes—APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. And 3.0% of non-Finnish European subjects in the Exome Aggregation Consortium had pathogenic mutations in these 12 genes.
Furthermore, 21 of the 61 BCC patients (64.4%) had a history of additional cancers. This included 5 hematologic malignancies (leukemia/lymphoma), 5 invasive melanomas, and 2 breast, 2 colon, and 5 prostate cancers.
When the researchers compared the cancer prevalence in these patients to the Surveillance, Epidemiology, and End Results-estimated prevalence of cancer in the 60- to 69-year-old population of European descent, the BCC cohort had an increased risk of any cancer—a relative risk (RR) of 3.5 (P<0.001).
The RR was 3.5 for leukemia and lymphoma (P=0.004), 11.9 for invasive melanoma (P<0.001), 4.5 for colon cancer (P=0.030), 5.6 for breast cancer (P=0.009), and 4.7 for prostate cancer (P<0.001).
Insurance cohort
To confirm the findings in the Stanford cohort, the researchers applied a similar analysis to a large medical insurance claims database, Truven MarketScan.
The database contained 111,562 patients with 1 case of BCC, 13,264 patients with 6 or more BCCs, and 2920 patients with 12 or more BCCs. Truven patients with no history of BCC served as controls.
The researchers adjusted for age and sex and found that patients with 1 BCC, 6 or more BCCs, and 12 or more BCCs had an increased risk of any cancer compared to controls.
The odds ratio (OR) for any cancer was 1.61 for patients with 1 BCC, 3.12 for those with 6 or more BCCs, and 4.15 for patients with 12 or more BCCs.
The OR for Hodgkin lymphoma was 2.27 for patients with 1 BCC, 8.94 for patients with 6 or more BCCs, and 15.41 for patients with 12 or more BCCs.
The OR for non-Hodgkin lymphoma was 1.40 for patients with 1 BCC, 2.59 for patients with 6 or more BCCs, and 3.10 for patients with 12 or more BCCs.
The OR for leukemia was 1.76 for patients with 1 BCC, 3.23 for patients with 6 or more BCCs, and 5.78 for patients with 12 or more BCCs.
The researchers pointed out that, the more BCCs an individual had, the more likely that person was to have had other cancers as well.
“I was surprised to see such a strong correlation, but it’s also very gratifying,” Dr Sarin said. “Now, we can ask patients with repeated basal cell carcinomas whether they have family members with other types of cancers and perhaps suggest that they consider genetic testing and increased screening.”
The researchers are continuing to enroll Stanford patients in their study to learn whether particular mutations in genes responsible for repairing DNA damage are linked to the development of specific malignancies. The team would also like to conduct a similar study in patients with frequent melanomas.
The current study was supported by the Dermatology Foundation, the Stanford Society of Physician Scholars, the American Skin Association, and Pellepharm Inc.
NIAAA Ends Funding for Alcohol and CV Health Study
After just 4 months, the National Institute of Alcohol Abuse and Alcoholism (NIAAA) is ending funding for the Moderate Alcohol and Cardiovascular Health (MACH) trial, citing concerns about the study design.
The MACH study was designed as a multicenter randomized trial to determine the effects of 1 serving of alcohol (approximately 15 g) a day compared with no alcohol intake on the rate of new cases of cardiovascular disease and new cases of diabetes among participants free of diabetes at baseline. The study was launched because some epidemiologic research had shown that moderate alcohol consumption had health benefits by reducing risk for coronary artery disease, type 2 diabetes, and rheumatoid arthritis.
The study began enrollment in February 2018 and was suspended on May 10. The NIAAA expected to commit $20 million to the project over 10 years, of which $4 million has been spent; remaining funding came from private donations of $67.7 million, of which $11.8 million has been spent.
The “orderly closeout” is based on recommendations from the advisory committee to the director working group, which found “significant process irregularities in the development of funding opportunities for the MACH funding awards undermined the integrity of the research process.” Additionally, a preliminary report from the National Institutes of Health (NIH) Office of Management Assessment determined that a small number of NIAAA employees violated NIH policies in soliciting gift funding and circumvented standard operating procedures.
After just 4 months, the National Institute of Alcohol Abuse and Alcoholism (NIAAA) is ending funding for the Moderate Alcohol and Cardiovascular Health (MACH) trial, citing concerns about the study design.
The MACH study was designed as a multicenter randomized trial to determine the effects of 1 serving of alcohol (approximately 15 g) a day compared with no alcohol intake on the rate of new cases of cardiovascular disease and new cases of diabetes among participants free of diabetes at baseline. The study was launched because some epidemiologic research had shown that moderate alcohol consumption had health benefits by reducing risk for coronary artery disease, type 2 diabetes, and rheumatoid arthritis.
The study began enrollment in February 2018 and was suspended on May 10. The NIAAA expected to commit $20 million to the project over 10 years, of which $4 million has been spent; remaining funding came from private donations of $67.7 million, of which $11.8 million has been spent.
The “orderly closeout” is based on recommendations from the advisory committee to the director working group, which found “significant process irregularities in the development of funding opportunities for the MACH funding awards undermined the integrity of the research process.” Additionally, a preliminary report from the National Institutes of Health (NIH) Office of Management Assessment determined that a small number of NIAAA employees violated NIH policies in soliciting gift funding and circumvented standard operating procedures.
After just 4 months, the National Institute of Alcohol Abuse and Alcoholism (NIAAA) is ending funding for the Moderate Alcohol and Cardiovascular Health (MACH) trial, citing concerns about the study design.
The MACH study was designed as a multicenter randomized trial to determine the effects of 1 serving of alcohol (approximately 15 g) a day compared with no alcohol intake on the rate of new cases of cardiovascular disease and new cases of diabetes among participants free of diabetes at baseline. The study was launched because some epidemiologic research had shown that moderate alcohol consumption had health benefits by reducing risk for coronary artery disease, type 2 diabetes, and rheumatoid arthritis.
The study began enrollment in February 2018 and was suspended on May 10. The NIAAA expected to commit $20 million to the project over 10 years, of which $4 million has been spent; remaining funding came from private donations of $67.7 million, of which $11.8 million has been spent.
The “orderly closeout” is based on recommendations from the advisory committee to the director working group, which found “significant process irregularities in the development of funding opportunities for the MACH funding awards undermined the integrity of the research process.” Additionally, a preliminary report from the National Institutes of Health (NIH) Office of Management Assessment determined that a small number of NIAAA employees violated NIH policies in soliciting gift funding and circumvented standard operating procedures.
Comprehensive sequencing informs treatment for MM
A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.
Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.
Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.
“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”
Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.
The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.
The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.
The treatments (given alone or in combination) were:
- Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
- Venetoclax (n=8)—recommended because of high BCL2 expression
- Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
- Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
- Etoposide (n=2)—selected by RNA-based drug repurposing.
Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.
One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.
That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).
The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).
Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.
“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.
“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”
A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.
Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.
Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.
“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”
Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.
The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.
The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.
The treatments (given alone or in combination) were:
- Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
- Venetoclax (n=8)—recommended because of high BCL2 expression
- Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
- Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
- Etoposide (n=2)—selected by RNA-based drug repurposing.
Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.
One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.
That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).
The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).
Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.
“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.
“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”
A comprehensive RNA and DNA sequencing platform can guide treatment decisions for late-stage and drug-resistant multiple myeloma (MM), according to a study published in JCO Precision Oncology.
Researchers used the platform to generate treatment suggestions for 64 MM patients who had exhausted all approved treatment options.
Of the 21 evaluable patients who received the sequencing-recommended therapies, 67% achieved a response. Five patients had ongoing responses at the end of the trial.
“Our study shows how a precision medicine approach incorporating RNA sequencing may identify viable and effective therapeutic options beyond the current FDA-approved armamentarium for multiple myeloma patients,” said study author Samir Parekh, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York.
“The trial has allowed us to test the accuracy of our platform, laying the foundation for our next-generation precision medicine framework.”
Dr Parekh and his colleagues used DNA and RNA sequencing data to generate personalized treatment recommendations for 64 heavily pretreated MM patients.
The patients had received a median of 7 lines of therapy. Most patients (61%) were male, their median age was 59 (range, 40-85), and 67% had high-risk cytogenetics.
The sequencing data yielded treatment recommendations for 63 patients. Twenty-six patients (42%) actually received at least 1 of the recommended treatments.
The treatments (given alone or in combination) were:
- Trametinib (n=16)—recommended because of mutations in NRAS or KRAS
- Venetoclax (n=8)—recommended because of high BCL2 expression
- Panobinostat (n=6)—recommended due to activation of the HDAC pathway and/or by RNA-based drug repurposing selecting the pan-HDAC inhibitor vorinostat
- Dabrafenib (n=1)—recommended because of concurrent BRAF and RAS mutations
- Etoposide (n=2)—selected by RNA-based drug repurposing.
Twenty-one patients were evaluable for response. The researchers noted that 11 of these patients received treatment based on RNA findings, 8 based on DNA, and 2 based on both.
One patient achieved a complete response, 3 had a very good partial response, 10 had a partial response, 2 had a minimal response (25% reduction of disease marker), 3 had stable disease, and 2 progressed.
That means the overall response rate was 66.6% (14/21), and the clinical benefit rate (minimal response or better) was 76.2% (16/21).
The median duration of response was 131 days (range, 37-372), and 5 patients were still in response at the end of the study (September, 1, 2017).
Mount Sinai researchers have received funding to develop a clinical trial that will incorporate machine learning algorithms into this precision medicine platform, which will implement interactive learning techniques to refine the predictions based on a patient’s success with the therapies and a physician’s opinion of the treatment plan.
“This research is part of an accelerating paradigm shift in cancer therapy where treatment may be given based on the specific genomic alterations observed in a patient’s tumor rather than on the tumor histology or tissue type,” said study author Joel Dudley, PhD, of the Icahn School of Medicine at Mount Sinai.
“RNA sequencing will likely complement current precision medicine strategies in the near future due to its ability to capture more dynamic aspects of unique tumor biology and provide information beyond what is capable with DNA alone.”
Tool identifies potential treatment for resistant MM
Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).
Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.
The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.
Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.
The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.
To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).
The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.
The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.
The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.
This revealed the top 3 combinations:
- Decitabine and mitomycin C
- Mechlorethamine hydrochloride, decitabine, and mitomycin C
- Bortezomib, mechlorethamine hydrochloride, and mitomycin C.
The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.
The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.
The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.
The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.
Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).
The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.
There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).
Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).
Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.
Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).
Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.
The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.
Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.
The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.
To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).
The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.
The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.
The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.
This revealed the top 3 combinations:
- Decitabine and mitomycin C
- Mechlorethamine hydrochloride, decitabine, and mitomycin C
- Bortezomib, mechlorethamine hydrochloride, and mitomycin C.
The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.
The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.
The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.
The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.
Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).
The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.
There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).
Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).
Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.
Researchers say they have developed a computational platform that can be used to identify optimal treatments for multiple myeloma (MM).
Using this tool, the quadratic phenotypic optimization platform (QPOP), the researchers identified a 2-drug combination that proved effective against bortezomib-resistant MM in vitro.
The combination—decitabine and mitomycin C—also decreased tumor volume and prolonged survival in a mouse model of bortezomib-resistant MM.
Masturah Bte Mohd Abdul Rashid, of the Cancer Science Institute of Singapore, and her colleagues reported these results in Science Translational Medicine.
The researchers explained that QPOP approximates biological responses to therapies using advanced mathematical equations. Unlike conventional models, QPOP doesn’t require predetermined information about the mechanisms or composition of a drug.
To test QPOP’s utility in MM, the researchers began by identifying candidate drugs that might be effective against bortezomib-resistant MM. They screened 114 approved oncology drugs on 2 MM cell lines—RPMI 8226 and bortezomib-resistant RPMI 8226 (P100v).
The drugs that proved most effective against P100v were dactinomycin, decitabine, mechlorethamine hydrochloride, and mitomycin C.
The researchers wanted to identify optimal drug combinations, so they conducted a QPOP analysis including the 4 most effective drugs and an additional 10 drugs used to treat MM. The 10 drugs were bortezomib, carfilzomib, cyclophosphamide monohydrate, dexamethasone, doxorubucin, lenalidomide, panobinostat, plerixafor, thalidomide, and zoledronic acid.
The team tested 2 dosages of the 14 drugs in 128 combinations, then narrowed the list to 9 drugs and tested them at 3 dosages in 155 combinations.
This revealed the top 3 combinations:
- Decitabine and mitomycin C
- Mechlorethamine hydrochloride, decitabine, and mitomycin C
- Bortezomib, mechlorethamine hydrochloride, and mitomycin C.
The researchers said these combinations act by reversing the DNA methylation and tumor suppressor silencing that often occurs after acquired bortezomib resistance.
The team noted that the top 3 combinations had synergistic interactions, but the QPOP analysis revealed antagonistic interactions as well. For example, bortezomib and dexamethasone proved antagonistic, as did bortezomib and panobinostat.
The researchers conducted further testing to determine the optimal dosage of decitabine and mitomycin C. Results suggested both drugs should be given at 1.5 mg/kg.
The team then treated P100v tumor-bearing mice with decitabine and mitomycin C, both at 1.5 mg/kg, either alone or in combination.
Mice that received the combination had a decrease in tumor size and prolonged survival compared to mice that received DMSO (P=0.0130), decitabine alone (P=0.0121), or mitomycin C alone (P=0.00174).
The researchers also compared decitabine and mitomycin C in combination to 2 bortezomib-based combinations used to treat MM—bortezomib/dexamethasone/melphalan and bortezomib/dexamethasone/lenalidomide—in P100v tumor-bearing mice.
There was a significant decrease in tumor volume with decitabine/mitomycin C compared to bortezomib/dexamethasone/melphalan (P=0.000376) and bortezomib/dexamethasone/lenalidomide (P=0.000691).
Mice that received decitabine/mitomycin C had significantly longer survival than mice that received bortezomib/dexamethasone/melphalan (P=0.0389) or bortezomib/dexamethasone/lenalidomide (P=0.0246).
Neither survival times nor tumor volumes were significantly different between the mice that received DMSO and those that received either of the bortezomib-based combinations.
RSV-related risk of hospitalization higher in Down syndrome patients
reported Andrea Beckhaus, MD, and Jose Castro-Rodriguez, MD, PhD, at the Pontificia Universidad Católica de Chile in Santiago.
Because DS is the most common chromosomal disorder, affecting 1 in every 800 children born worldwide, and respiratory infections are the leading cause of hospitalization in children with DS, especially during the first year of life, the results of this study are important and have considerable consequences for public health, the authors observed.
The economic burden on families of children with DS and the health care systems that treat them is, not surprisingly, significantly higher given their sevenfold higher need for supplemental oxygen therapy, threefold likely increased risk of ICU admission, fivefold higher likely need for ventilator support, and average increased length of hospital stay by nearly 5 days.
In the 15 years from 1997 to 2012, RSV-related hospital charges for infants with DS increased by nearly 80% from $10,141 (US dollars) to $18,217, compared with charges for infants not at high risk, which increased by more than 60% from $6,983 to $11,273 during the same period, according to a study (PLoS One. 2016;11[4]:e0152208).
Dr. Beckhaus and Dr. Castro-Rodriguez conducted their systematic review and meta-analysis to evaluate RSV-associated morbidity in children with DS. Following a search of four electronic data bases, a total of 12 studies published between 2004 and 2017 across 10 different countries were identified, including six in Europe, three in Asia, two in the United States, and one in Latin America. Altogether, 3,662 children with DS and 1,145,509 without DS were included in the review.
“Any potential strategy to reduce RSV infection (e.g., prophylaxis with monoclonal antibodies or new vaccines) in children with DS could decrease their morbidity and mortality,” the authors noted. Specifically, they cited the humanized monoclonal antibody palivizumab, which is used for prophylaxis against RSV. Palivizumab is known to reduce hospitalizations in children at high risk from comorbid conditions, including chronic lung disease, hemodynamically significant congenital heart disease (CHD), neuromuscular disease, immunodeficiency, and prematurity. At present, palivizumab is not recommended by the American Academy of Pediatrics for routine use to prevent RSV infection in patients with DS who are not already qualified for other reasons because there are insufficient data to recommend routine prophylactic use of the drug in children with Down syndrome.
The authors cited recent studies in Canada and Japan that may warrant further reconsideration of the AAP’s recommendations, however. A fourfold lowering of RSV-related hospitalizations was observed during the first 2 years of life among 532 children with DS receiving palivizumab who were included in a recent prospective Canadian study. The drug also was found to be safe and effective for preventing lower respiratory tract infections caused by RSV in a recent Japanese multicenter postmarketing surveillance study that evaluated palivizumab prophylaxis for RSV infection in 138 children with DS who did not have hemodynamically significant CHD; only 2 of the children treated required hospitalization.
“More cost-utility studies used to determine the efficacy of RSV immunoprophylaxis in this specific high-risk patient population need to be done,” Dr. Beckhaus and Dr. Castro-Rodriguez recommended.
The review was not without limitations. Not all of the studies included subgroups of participants with DS with CHD and without CHD or other additional risk factors. However, when only those studies were considered that had data for participants with DS without other risk factors, almost all results were similar.
One key strength of the study concerned the study methodology. Using the Newcastle–Ottawa scale, the risk of bias among the 12 studies was generally low, the total number of participants was considerably high, and the outcomes selected had importance for the patients and also public health implications. “It is important to remark that the vast majority of the outcomes that were analyzed had no or unimportant bias,” they said.
Dr. Beckhaus and Dr. Castro-Rodriguez had no relevant disclosures to disclose.
SOURCE: Beckhaus A et al. J Pediatrics. 2018;142(3):e20180225.
reported Andrea Beckhaus, MD, and Jose Castro-Rodriguez, MD, PhD, at the Pontificia Universidad Católica de Chile in Santiago.
Because DS is the most common chromosomal disorder, affecting 1 in every 800 children born worldwide, and respiratory infections are the leading cause of hospitalization in children with DS, especially during the first year of life, the results of this study are important and have considerable consequences for public health, the authors observed.
The economic burden on families of children with DS and the health care systems that treat them is, not surprisingly, significantly higher given their sevenfold higher need for supplemental oxygen therapy, threefold likely increased risk of ICU admission, fivefold higher likely need for ventilator support, and average increased length of hospital stay by nearly 5 days.
In the 15 years from 1997 to 2012, RSV-related hospital charges for infants with DS increased by nearly 80% from $10,141 (US dollars) to $18,217, compared with charges for infants not at high risk, which increased by more than 60% from $6,983 to $11,273 during the same period, according to a study (PLoS One. 2016;11[4]:e0152208).
Dr. Beckhaus and Dr. Castro-Rodriguez conducted their systematic review and meta-analysis to evaluate RSV-associated morbidity in children with DS. Following a search of four electronic data bases, a total of 12 studies published between 2004 and 2017 across 10 different countries were identified, including six in Europe, three in Asia, two in the United States, and one in Latin America. Altogether, 3,662 children with DS and 1,145,509 without DS were included in the review.
“Any potential strategy to reduce RSV infection (e.g., prophylaxis with monoclonal antibodies or new vaccines) in children with DS could decrease their morbidity and mortality,” the authors noted. Specifically, they cited the humanized monoclonal antibody palivizumab, which is used for prophylaxis against RSV. Palivizumab is known to reduce hospitalizations in children at high risk from comorbid conditions, including chronic lung disease, hemodynamically significant congenital heart disease (CHD), neuromuscular disease, immunodeficiency, and prematurity. At present, palivizumab is not recommended by the American Academy of Pediatrics for routine use to prevent RSV infection in patients with DS who are not already qualified for other reasons because there are insufficient data to recommend routine prophylactic use of the drug in children with Down syndrome.
The authors cited recent studies in Canada and Japan that may warrant further reconsideration of the AAP’s recommendations, however. A fourfold lowering of RSV-related hospitalizations was observed during the first 2 years of life among 532 children with DS receiving palivizumab who were included in a recent prospective Canadian study. The drug also was found to be safe and effective for preventing lower respiratory tract infections caused by RSV in a recent Japanese multicenter postmarketing surveillance study that evaluated palivizumab prophylaxis for RSV infection in 138 children with DS who did not have hemodynamically significant CHD; only 2 of the children treated required hospitalization.
“More cost-utility studies used to determine the efficacy of RSV immunoprophylaxis in this specific high-risk patient population need to be done,” Dr. Beckhaus and Dr. Castro-Rodriguez recommended.
The review was not without limitations. Not all of the studies included subgroups of participants with DS with CHD and without CHD or other additional risk factors. However, when only those studies were considered that had data for participants with DS without other risk factors, almost all results were similar.
One key strength of the study concerned the study methodology. Using the Newcastle–Ottawa scale, the risk of bias among the 12 studies was generally low, the total number of participants was considerably high, and the outcomes selected had importance for the patients and also public health implications. “It is important to remark that the vast majority of the outcomes that were analyzed had no or unimportant bias,” they said.
Dr. Beckhaus and Dr. Castro-Rodriguez had no relevant disclosures to disclose.
SOURCE: Beckhaus A et al. J Pediatrics. 2018;142(3):e20180225.
reported Andrea Beckhaus, MD, and Jose Castro-Rodriguez, MD, PhD, at the Pontificia Universidad Católica de Chile in Santiago.
Because DS is the most common chromosomal disorder, affecting 1 in every 800 children born worldwide, and respiratory infections are the leading cause of hospitalization in children with DS, especially during the first year of life, the results of this study are important and have considerable consequences for public health, the authors observed.
The economic burden on families of children with DS and the health care systems that treat them is, not surprisingly, significantly higher given their sevenfold higher need for supplemental oxygen therapy, threefold likely increased risk of ICU admission, fivefold higher likely need for ventilator support, and average increased length of hospital stay by nearly 5 days.
In the 15 years from 1997 to 2012, RSV-related hospital charges for infants with DS increased by nearly 80% from $10,141 (US dollars) to $18,217, compared with charges for infants not at high risk, which increased by more than 60% from $6,983 to $11,273 during the same period, according to a study (PLoS One. 2016;11[4]:e0152208).
Dr. Beckhaus and Dr. Castro-Rodriguez conducted their systematic review and meta-analysis to evaluate RSV-associated morbidity in children with DS. Following a search of four electronic data bases, a total of 12 studies published between 2004 and 2017 across 10 different countries were identified, including six in Europe, three in Asia, two in the United States, and one in Latin America. Altogether, 3,662 children with DS and 1,145,509 without DS were included in the review.
“Any potential strategy to reduce RSV infection (e.g., prophylaxis with monoclonal antibodies or new vaccines) in children with DS could decrease their morbidity and mortality,” the authors noted. Specifically, they cited the humanized monoclonal antibody palivizumab, which is used for prophylaxis against RSV. Palivizumab is known to reduce hospitalizations in children at high risk from comorbid conditions, including chronic lung disease, hemodynamically significant congenital heart disease (CHD), neuromuscular disease, immunodeficiency, and prematurity. At present, palivizumab is not recommended by the American Academy of Pediatrics for routine use to prevent RSV infection in patients with DS who are not already qualified for other reasons because there are insufficient data to recommend routine prophylactic use of the drug in children with Down syndrome.
The authors cited recent studies in Canada and Japan that may warrant further reconsideration of the AAP’s recommendations, however. A fourfold lowering of RSV-related hospitalizations was observed during the first 2 years of life among 532 children with DS receiving palivizumab who were included in a recent prospective Canadian study. The drug also was found to be safe and effective for preventing lower respiratory tract infections caused by RSV in a recent Japanese multicenter postmarketing surveillance study that evaluated palivizumab prophylaxis for RSV infection in 138 children with DS who did not have hemodynamically significant CHD; only 2 of the children treated required hospitalization.
“More cost-utility studies used to determine the efficacy of RSV immunoprophylaxis in this specific high-risk patient population need to be done,” Dr. Beckhaus and Dr. Castro-Rodriguez recommended.
The review was not without limitations. Not all of the studies included subgroups of participants with DS with CHD and without CHD or other additional risk factors. However, when only those studies were considered that had data for participants with DS without other risk factors, almost all results were similar.
One key strength of the study concerned the study methodology. Using the Newcastle–Ottawa scale, the risk of bias among the 12 studies was generally low, the total number of participants was considerably high, and the outcomes selected had importance for the patients and also public health implications. “It is important to remark that the vast majority of the outcomes that were analyzed had no or unimportant bias,” they said.
Dr. Beckhaus and Dr. Castro-Rodriguez had no relevant disclosures to disclose.
SOURCE: Beckhaus A et al. J Pediatrics. 2018;142(3):e20180225.
FROM PEDIATRICS
Key clinical point: Strategies to reduce RSV are needed to decrease morbidity and mortality in children with Down syndrome.
Major finding: Down syndrome children with RSV-related hospitalization had sevenfold higher need for supplemental oxygen therapy, threefold likely increased risk of ICU admission, fivefold higher likely need for ventilator support, and average increased length of hospital stay by nearly 5 days.
Study details: Systematic review and 12-study meta-analysis of 3,662 children with DS and 1,145,509 without DS.
Disclosures: The authors had no relevant financial disclosures.
Source: Beckhaus A et al. J Pediatrics. 2018;142(3):e20180225.
Maternal obesity plus diabetes lead to psychiatric disorders in offspring
Women who were obese and had diabetes before becoming pregnant were sixfold more likely to have children with psychiatric and neurodevelopmental disorders by age 11 years, as compared to women with normal body mass indexes (BMIs), based on results of a large, prospective, population-based, cohort study published in Pediatrics.
The risks to offspring whose mothers were obese and had pregestational diabetes mellitus (PGDM) were far greater than the risks seen when mothers had either condition alone or had gestational diabetes mellitus (GDM) in the study, reported Linghua Kong of the Karolinska Institute, Stockholm, and colleagues. The study is based on data from various national registries in Finland regarding 649,043 live births during 2004-2014 and data regarding psychiatric diagnoses from the Finnish Care Registers for Health Care.
Of the children in the cohort, 7.67% had mothers who were obese and 3.66% had mothers who were severely obese based on standard World Health Organization criteria; mothers had PGDM in 0.62% of the births and GDM in 15.7% of the births.
Overall, 5.4% of the children were diagnosed with a psychiatric disorder by age 11 years.
Compared with children born to mothers of normal weight (BMI less than 25 kg/m2), those born to mothers with severe maternal obesity alone (BMI greater than 35) had higher rates of developmental disorders or speech, language, motor, and scholastic skills (hazard ratio, 1.69; 95% confidence interval 1.54-1.86); ADHD and/or conduct disorder (HR, 1.88; 95% CI, 1.58-2.23); and psychosis and mood and anxiety disorders (HR, 1.67; 95% CI, 1.31-2.13). Increased risk of psychiatric disorders were only slightly statistically significant in the offspring of women with severe obesity and GDM.
The risks were significantly elevated, however, for children born to obese women who also had PGDM. The hazard ratio for autism spectrum disorder was 6.49 (95% CI, 3.08-13.69), and the HR for ADHD and/or conduct disorder was 6.03 (95% CI, 3.23-11.24). The risks were fourfold higher for mixed disorders of emotions and conduct, disorders of social function, and tics (HR, 4.29; 95% CI, 2.14-8.60).
Limitations of the study included basing results on shorter follow-up times for those born later in the study period, grouping of offspring’s disorder diagnoses, basing the definition of PGDM on insulin prescription, and using BMI measurements taken at only one time point during pregnancy.
The researchers were supported by the National Institute for Health and Welfare: Drugs and Pregnancy project, the Swedish Research Council, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet Stockholm County Council, the China Scholarship Council, and the Swedish Brain Foundation.
SOURCE: Kong L et al. Pediatrics. 2018 Sep;142(3):1-11.
Women who were obese and had diabetes before becoming pregnant were sixfold more likely to have children with psychiatric and neurodevelopmental disorders by age 11 years, as compared to women with normal body mass indexes (BMIs), based on results of a large, prospective, population-based, cohort study published in Pediatrics.
The risks to offspring whose mothers were obese and had pregestational diabetes mellitus (PGDM) were far greater than the risks seen when mothers had either condition alone or had gestational diabetes mellitus (GDM) in the study, reported Linghua Kong of the Karolinska Institute, Stockholm, and colleagues. The study is based on data from various national registries in Finland regarding 649,043 live births during 2004-2014 and data regarding psychiatric diagnoses from the Finnish Care Registers for Health Care.
Of the children in the cohort, 7.67% had mothers who were obese and 3.66% had mothers who were severely obese based on standard World Health Organization criteria; mothers had PGDM in 0.62% of the births and GDM in 15.7% of the births.
Overall, 5.4% of the children were diagnosed with a psychiatric disorder by age 11 years.
Compared with children born to mothers of normal weight (BMI less than 25 kg/m2), those born to mothers with severe maternal obesity alone (BMI greater than 35) had higher rates of developmental disorders or speech, language, motor, and scholastic skills (hazard ratio, 1.69; 95% confidence interval 1.54-1.86); ADHD and/or conduct disorder (HR, 1.88; 95% CI, 1.58-2.23); and psychosis and mood and anxiety disorders (HR, 1.67; 95% CI, 1.31-2.13). Increased risk of psychiatric disorders were only slightly statistically significant in the offspring of women with severe obesity and GDM.
The risks were significantly elevated, however, for children born to obese women who also had PGDM. The hazard ratio for autism spectrum disorder was 6.49 (95% CI, 3.08-13.69), and the HR for ADHD and/or conduct disorder was 6.03 (95% CI, 3.23-11.24). The risks were fourfold higher for mixed disorders of emotions and conduct, disorders of social function, and tics (HR, 4.29; 95% CI, 2.14-8.60).
Limitations of the study included basing results on shorter follow-up times for those born later in the study period, grouping of offspring’s disorder diagnoses, basing the definition of PGDM on insulin prescription, and using BMI measurements taken at only one time point during pregnancy.
The researchers were supported by the National Institute for Health and Welfare: Drugs and Pregnancy project, the Swedish Research Council, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet Stockholm County Council, the China Scholarship Council, and the Swedish Brain Foundation.
SOURCE: Kong L et al. Pediatrics. 2018 Sep;142(3):1-11.
Women who were obese and had diabetes before becoming pregnant were sixfold more likely to have children with psychiatric and neurodevelopmental disorders by age 11 years, as compared to women with normal body mass indexes (BMIs), based on results of a large, prospective, population-based, cohort study published in Pediatrics.
The risks to offspring whose mothers were obese and had pregestational diabetes mellitus (PGDM) were far greater than the risks seen when mothers had either condition alone or had gestational diabetes mellitus (GDM) in the study, reported Linghua Kong of the Karolinska Institute, Stockholm, and colleagues. The study is based on data from various national registries in Finland regarding 649,043 live births during 2004-2014 and data regarding psychiatric diagnoses from the Finnish Care Registers for Health Care.
Of the children in the cohort, 7.67% had mothers who were obese and 3.66% had mothers who were severely obese based on standard World Health Organization criteria; mothers had PGDM in 0.62% of the births and GDM in 15.7% of the births.
Overall, 5.4% of the children were diagnosed with a psychiatric disorder by age 11 years.
Compared with children born to mothers of normal weight (BMI less than 25 kg/m2), those born to mothers with severe maternal obesity alone (BMI greater than 35) had higher rates of developmental disorders or speech, language, motor, and scholastic skills (hazard ratio, 1.69; 95% confidence interval 1.54-1.86); ADHD and/or conduct disorder (HR, 1.88; 95% CI, 1.58-2.23); and psychosis and mood and anxiety disorders (HR, 1.67; 95% CI, 1.31-2.13). Increased risk of psychiatric disorders were only slightly statistically significant in the offspring of women with severe obesity and GDM.
The risks were significantly elevated, however, for children born to obese women who also had PGDM. The hazard ratio for autism spectrum disorder was 6.49 (95% CI, 3.08-13.69), and the HR for ADHD and/or conduct disorder was 6.03 (95% CI, 3.23-11.24). The risks were fourfold higher for mixed disorders of emotions and conduct, disorders of social function, and tics (HR, 4.29; 95% CI, 2.14-8.60).
Limitations of the study included basing results on shorter follow-up times for those born later in the study period, grouping of offspring’s disorder diagnoses, basing the definition of PGDM on insulin prescription, and using BMI measurements taken at only one time point during pregnancy.
The researchers were supported by the National Institute for Health and Welfare: Drugs and Pregnancy project, the Swedish Research Council, the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet Stockholm County Council, the China Scholarship Council, and the Swedish Brain Foundation.
SOURCE: Kong L et al. Pediatrics. 2018 Sep;142(3):1-11.
FROM PEDIATRICS
Scaling lesions on arm
The FP also was concerned about a possible skin cancer, especially for the larger of the 2 lesions. The FP recommended 2 shave biopsies, which the patient agreed to. (See the Watch & Learn video on “Shave biopsy.”) The patient was directed to apply petrolatum once or twice daily to the biopsy sites and to cover them with dressings for the next 1 to 2 weeks. On the 2-week follow-up, the physician diagnosed the larger lesion as squamous cell carcinoma in situ (Bowen disease) and the top lesion as actinic keratosis.
The physician explained that the actinic keratosis did not need further treatment; however, the options for treating Bowen disease included cryosurgery, electrodesiccation and curettage, or elliptical excision. The patient chose an elliptical excision, which was performed without complications at the following visit.
The margins were clear and the surgery site healed without any problems. The patient said that he planned to wear long sleeves more often and use sunscreen when his arms were exposed to the sun.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Wah Y. Actinic keratosis and Bowen disease. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:969-976.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.
The FP also was concerned about a possible skin cancer, especially for the larger of the 2 lesions. The FP recommended 2 shave biopsies, which the patient agreed to. (See the Watch & Learn video on “Shave biopsy.”) The patient was directed to apply petrolatum once or twice daily to the biopsy sites and to cover them with dressings for the next 1 to 2 weeks. On the 2-week follow-up, the physician diagnosed the larger lesion as squamous cell carcinoma in situ (Bowen disease) and the top lesion as actinic keratosis.
The physician explained that the actinic keratosis did not need further treatment; however, the options for treating Bowen disease included cryosurgery, electrodesiccation and curettage, or elliptical excision. The patient chose an elliptical excision, which was performed without complications at the following visit.
The margins were clear and the surgery site healed without any problems. The patient said that he planned to wear long sleeves more often and use sunscreen when his arms were exposed to the sun.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Wah Y. Actinic keratosis and Bowen disease. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:969-976.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.
The FP also was concerned about a possible skin cancer, especially for the larger of the 2 lesions. The FP recommended 2 shave biopsies, which the patient agreed to. (See the Watch & Learn video on “Shave biopsy.”) The patient was directed to apply petrolatum once or twice daily to the biopsy sites and to cover them with dressings for the next 1 to 2 weeks. On the 2-week follow-up, the physician diagnosed the larger lesion as squamous cell carcinoma in situ (Bowen disease) and the top lesion as actinic keratosis.
The physician explained that the actinic keratosis did not need further treatment; however, the options for treating Bowen disease included cryosurgery, electrodesiccation and curettage, or elliptical excision. The patient chose an elliptical excision, which was performed without complications at the following visit.
The margins were clear and the surgery site healed without any problems. The patient said that he planned to wear long sleeves more often and use sunscreen when his arms were exposed to the sun.
Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R, Wah Y. Actinic keratosis and Bowen disease. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:969-976.
To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.
You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.
FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis
Psychosis and stroke are arguably the most serious acute threats to the integrity of the brain, and consequently the mind. Both are unquestionably associated with a grave outcome the longer their treatment is delayed.1,2
While the management of stroke has been elevated to the highest emergent priority because of the progressively deleterious impact of thrombotic ischemia in one of the cerebral arteries, rapid intervention for acute psychosis has never been regarded as an urgent neurologic condition with severe threats to the brain’s structure and function.3,4 There is extensive literature on the serious consequences of a long duration of untreated psychosis (DUP), including treatment resistance, frequent re-hospitalizations, more negative symptoms, and greater disability.5
Physical paralysis from a stroke receives much more attention than “mental paralysis” of psychosis. Both must be rapidly treated, whether for the regional ischemia to brain tissue following a stroke or for the neurotoxicity of neuroinflammation and oxidative stress that lead to widespread neurodegeneration during psychosis.6 While an acronym for the quick recognition of a stroke (FAST: Facial drooping, Arm weakness, Speech difficulties, and Time to call emergency services) is well established, no acronym for the urgency to treat psychosis has been developed. We propose the acronym RAPID (Readily Avoid Psychosis-Induced Damage). The acronym RAPID would hopefully expedite the urgently needed pharmacotherapeutic and psychosocial intervention in psychosis to halt ongoing brain tissue loss.
It is ironic that the legal obstacles for immediate treatment, which do not exist for stroke, often delay administering antipsychotic medication to patients with anosognosia (a neurologic delusional belief that one is not ill, leading to refusal of treatment) for their psychosis and end up harming patients by prolonging their DUP until a court order is obtained to force brain-saving treatment. Frequent psychotic relapses due to nonadherence with medications are also a very common cause for prolonged DUP due to the inexplicable reluctance of some psychiatric practitioners to employ a long-acting injectable antipsychotic (LAI) medication as soon as possible after the onset of psychosis to circumvent subsequent relapses due to the very high risk of poor adherence. Table 1 describes the optimal management of both stroke and acute psychosis once they are rapidly diagnosed, thanks to the FAST and RAPID reminders.
Tragically, the treatments of the mind have become falsely disengaged from the brain, the physical organ whose neurons, electrical impulses, synapses, and neurotransmitters generate the mind with its advanced human functions, such as self-awareness, will, thoughts, mood, speech, executive functions, memories, and social cognition. Recent editorials have challenged psychiatric practitioners to behave like cardiologists7 and oncologists8 by aggressively treating first-episode psychosis to prevent ongoing neurodegeneration due to recurrences. The brain loses 1% of its brain volume (~11 ml) after the first psychotic episode,8 which represents hundreds of millions of cells, billions of synapses, and substantial myelin. A second psychotic episode causes significant additional neuropil and white matter fiber damage and represents a different stage of schizophrenia9 with more severe tissue loss and disruption of neural pathways that trigger the process of treatment resistance and functional disability. Ensuring adherence with LAI antipsychotic formulations immediately after the first psychotic episode may allow many patients with schizophrenia to achieve a relapse-free remission and to return to their baseline functioning.10
In addition to significant brain tissue loss during psychotic episodes, mortality is also a very high risk following discharge from the first hospitalization for psychosis.11 LAI second-generation antipsychotic medications have been shown to be associated with lower mortality and neuroprotective effects,12 compared with oral or injectable first-generation antipsychotics. The highest mortality rate was reported to be associated with the lack of any antipsychotic medication,12 underscoring how untreated psychosis can be fatal.
Bottom line: Rapid treatment of stroke and psychosis is an absolute imperative for minimizing brain damage that respectively leads to physical or mental disability. The acronyms FAST and RAPID are essential reminders of the urgency needed to halt progressive neurodegeneration in those 2 devastating acute threats to the integrity of brain and mind. Intensive physical, psychological, and social rehabilitation must follow the acute treatment of stroke and psychosis, and the prevention of any recurrence is an absolute must. For psychosis, the use of a LAI second-generation antipsychotic before hospital discharge from a first episode of psychosis can be disease-modifying, with a more benign illness trajectory and outcome than the devastating deterioration that follows repetitive psychotic relapse, most often due to nonadherence with oral medications.
Continue to: Psychosis should be conceptualized as...
Psychosis should be conceptualized as a “stroke of the mind,” and it can be prevented in most patients with schizophrenia by adopting injectable antipsychotics as early after the onset of psychosis as possible. Yet, starting a LAI antipsychotic drug in first-episode psychosis before hospital discharge is rarely done, and the few patients who currently receive LAIs (10% of U.S. patients) generally receive them after multiple episodes and a protracted DUP. That’s like calling the fire department when much of the house has turned to ashes, instead of calling them when the first small flame is noticed. It makes so much sense, but the decades-old practice of postponing the use of LAIs continues to ruin the lives of young persons in the prime of life. By changing our practice habits to early use of LAIs, we have nothing to lose and our patients with psychosis may be spared a lifetime of suffering, poverty, stigma, incarceration, and functional disability. Wouldn’t we want to avoid that atrocious outcome for our own family members if they develop schizophrenia?
1. Benjamin EJ, Virani SS, Callaway CW, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492.
2. Cechnicki A, Cichocki Ł, Kalisz A, et al. Duration of untreated psychosis (DUP) and the course of schizophrenia in a 20-year follow-up study. Psychiatry Res. 2014;219(3):420-425.
3. Davis J, Moylan S, Harvey BH, et al. Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014;48(6):512-529.
4. Olabi B, Ellison-Wright I, McIntosh AM, et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry. 2011;70(1):88-96.
5. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE Early Treatment Program. Am J Psychiatry. 2016;173(4):362-372.
6. Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015;161(1):102-112.
7. Nasrallah HA. For first-episode psychosis, psychiatrists should behave like cardiologists. Current Psychiatry. 2017;16(8):4-7.
8. Cahn W, Hulshoff Pol HE, Lems EB, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry. 2002;59(11):1002-1010.
9. McGorry P, Nelson B. Why we need a transdiagnostic staging approach to emerging psychopathology, early diagnosis, and treatment. JAMA Psychiatry. 2016;73(3):191-192.
10. Emsley R, Oosthuizen P, Koen L, et al. Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection. Int Clin Psychopharmacol. 2008;23(6):325-331.
11. Nasrallah HA. The crisis of poor physical health and early mortality of psychiatric patients. Current Psychiatry. 2018;17(4):7-8,11.
12. Nasrallah HA. Triple advantages of injectable long acting second generation antipsychotics: relapse prevention, neuroprotection, and lower mortality. Schizophr Res. 2018;197:69-70.
Psychosis and stroke are arguably the most serious acute threats to the integrity of the brain, and consequently the mind. Both are unquestionably associated with a grave outcome the longer their treatment is delayed.1,2
While the management of stroke has been elevated to the highest emergent priority because of the progressively deleterious impact of thrombotic ischemia in one of the cerebral arteries, rapid intervention for acute psychosis has never been regarded as an urgent neurologic condition with severe threats to the brain’s structure and function.3,4 There is extensive literature on the serious consequences of a long duration of untreated psychosis (DUP), including treatment resistance, frequent re-hospitalizations, more negative symptoms, and greater disability.5
Physical paralysis from a stroke receives much more attention than “mental paralysis” of psychosis. Both must be rapidly treated, whether for the regional ischemia to brain tissue following a stroke or for the neurotoxicity of neuroinflammation and oxidative stress that lead to widespread neurodegeneration during psychosis.6 While an acronym for the quick recognition of a stroke (FAST: Facial drooping, Arm weakness, Speech difficulties, and Time to call emergency services) is well established, no acronym for the urgency to treat psychosis has been developed. We propose the acronym RAPID (Readily Avoid Psychosis-Induced Damage). The acronym RAPID would hopefully expedite the urgently needed pharmacotherapeutic and psychosocial intervention in psychosis to halt ongoing brain tissue loss.
It is ironic that the legal obstacles for immediate treatment, which do not exist for stroke, often delay administering antipsychotic medication to patients with anosognosia (a neurologic delusional belief that one is not ill, leading to refusal of treatment) for their psychosis and end up harming patients by prolonging their DUP until a court order is obtained to force brain-saving treatment. Frequent psychotic relapses due to nonadherence with medications are also a very common cause for prolonged DUP due to the inexplicable reluctance of some psychiatric practitioners to employ a long-acting injectable antipsychotic (LAI) medication as soon as possible after the onset of psychosis to circumvent subsequent relapses due to the very high risk of poor adherence. Table 1 describes the optimal management of both stroke and acute psychosis once they are rapidly diagnosed, thanks to the FAST and RAPID reminders.
Tragically, the treatments of the mind have become falsely disengaged from the brain, the physical organ whose neurons, electrical impulses, synapses, and neurotransmitters generate the mind with its advanced human functions, such as self-awareness, will, thoughts, mood, speech, executive functions, memories, and social cognition. Recent editorials have challenged psychiatric practitioners to behave like cardiologists7 and oncologists8 by aggressively treating first-episode psychosis to prevent ongoing neurodegeneration due to recurrences. The brain loses 1% of its brain volume (~11 ml) after the first psychotic episode,8 which represents hundreds of millions of cells, billions of synapses, and substantial myelin. A second psychotic episode causes significant additional neuropil and white matter fiber damage and represents a different stage of schizophrenia9 with more severe tissue loss and disruption of neural pathways that trigger the process of treatment resistance and functional disability. Ensuring adherence with LAI antipsychotic formulations immediately after the first psychotic episode may allow many patients with schizophrenia to achieve a relapse-free remission and to return to their baseline functioning.10
In addition to significant brain tissue loss during psychotic episodes, mortality is also a very high risk following discharge from the first hospitalization for psychosis.11 LAI second-generation antipsychotic medications have been shown to be associated with lower mortality and neuroprotective effects,12 compared with oral or injectable first-generation antipsychotics. The highest mortality rate was reported to be associated with the lack of any antipsychotic medication,12 underscoring how untreated psychosis can be fatal.
Bottom line: Rapid treatment of stroke and psychosis is an absolute imperative for minimizing brain damage that respectively leads to physical or mental disability. The acronyms FAST and RAPID are essential reminders of the urgency needed to halt progressive neurodegeneration in those 2 devastating acute threats to the integrity of brain and mind. Intensive physical, psychological, and social rehabilitation must follow the acute treatment of stroke and psychosis, and the prevention of any recurrence is an absolute must. For psychosis, the use of a LAI second-generation antipsychotic before hospital discharge from a first episode of psychosis can be disease-modifying, with a more benign illness trajectory and outcome than the devastating deterioration that follows repetitive psychotic relapse, most often due to nonadherence with oral medications.
Continue to: Psychosis should be conceptualized as...
Psychosis should be conceptualized as a “stroke of the mind,” and it can be prevented in most patients with schizophrenia by adopting injectable antipsychotics as early after the onset of psychosis as possible. Yet, starting a LAI antipsychotic drug in first-episode psychosis before hospital discharge is rarely done, and the few patients who currently receive LAIs (10% of U.S. patients) generally receive them after multiple episodes and a protracted DUP. That’s like calling the fire department when much of the house has turned to ashes, instead of calling them when the first small flame is noticed. It makes so much sense, but the decades-old practice of postponing the use of LAIs continues to ruin the lives of young persons in the prime of life. By changing our practice habits to early use of LAIs, we have nothing to lose and our patients with psychosis may be spared a lifetime of suffering, poverty, stigma, incarceration, and functional disability. Wouldn’t we want to avoid that atrocious outcome for our own family members if they develop schizophrenia?
Psychosis and stroke are arguably the most serious acute threats to the integrity of the brain, and consequently the mind. Both are unquestionably associated with a grave outcome the longer their treatment is delayed.1,2
While the management of stroke has been elevated to the highest emergent priority because of the progressively deleterious impact of thrombotic ischemia in one of the cerebral arteries, rapid intervention for acute psychosis has never been regarded as an urgent neurologic condition with severe threats to the brain’s structure and function.3,4 There is extensive literature on the serious consequences of a long duration of untreated psychosis (DUP), including treatment resistance, frequent re-hospitalizations, more negative symptoms, and greater disability.5
Physical paralysis from a stroke receives much more attention than “mental paralysis” of psychosis. Both must be rapidly treated, whether for the regional ischemia to brain tissue following a stroke or for the neurotoxicity of neuroinflammation and oxidative stress that lead to widespread neurodegeneration during psychosis.6 While an acronym for the quick recognition of a stroke (FAST: Facial drooping, Arm weakness, Speech difficulties, and Time to call emergency services) is well established, no acronym for the urgency to treat psychosis has been developed. We propose the acronym RAPID (Readily Avoid Psychosis-Induced Damage). The acronym RAPID would hopefully expedite the urgently needed pharmacotherapeutic and psychosocial intervention in psychosis to halt ongoing brain tissue loss.
It is ironic that the legal obstacles for immediate treatment, which do not exist for stroke, often delay administering antipsychotic medication to patients with anosognosia (a neurologic delusional belief that one is not ill, leading to refusal of treatment) for their psychosis and end up harming patients by prolonging their DUP until a court order is obtained to force brain-saving treatment. Frequent psychotic relapses due to nonadherence with medications are also a very common cause for prolonged DUP due to the inexplicable reluctance of some psychiatric practitioners to employ a long-acting injectable antipsychotic (LAI) medication as soon as possible after the onset of psychosis to circumvent subsequent relapses due to the very high risk of poor adherence. Table 1 describes the optimal management of both stroke and acute psychosis once they are rapidly diagnosed, thanks to the FAST and RAPID reminders.
Tragically, the treatments of the mind have become falsely disengaged from the brain, the physical organ whose neurons, electrical impulses, synapses, and neurotransmitters generate the mind with its advanced human functions, such as self-awareness, will, thoughts, mood, speech, executive functions, memories, and social cognition. Recent editorials have challenged psychiatric practitioners to behave like cardiologists7 and oncologists8 by aggressively treating first-episode psychosis to prevent ongoing neurodegeneration due to recurrences. The brain loses 1% of its brain volume (~11 ml) after the first psychotic episode,8 which represents hundreds of millions of cells, billions of synapses, and substantial myelin. A second psychotic episode causes significant additional neuropil and white matter fiber damage and represents a different stage of schizophrenia9 with more severe tissue loss and disruption of neural pathways that trigger the process of treatment resistance and functional disability. Ensuring adherence with LAI antipsychotic formulations immediately after the first psychotic episode may allow many patients with schizophrenia to achieve a relapse-free remission and to return to their baseline functioning.10
In addition to significant brain tissue loss during psychotic episodes, mortality is also a very high risk following discharge from the first hospitalization for psychosis.11 LAI second-generation antipsychotic medications have been shown to be associated with lower mortality and neuroprotective effects,12 compared with oral or injectable first-generation antipsychotics. The highest mortality rate was reported to be associated with the lack of any antipsychotic medication,12 underscoring how untreated psychosis can be fatal.
Bottom line: Rapid treatment of stroke and psychosis is an absolute imperative for minimizing brain damage that respectively leads to physical or mental disability. The acronyms FAST and RAPID are essential reminders of the urgency needed to halt progressive neurodegeneration in those 2 devastating acute threats to the integrity of brain and mind. Intensive physical, psychological, and social rehabilitation must follow the acute treatment of stroke and psychosis, and the prevention of any recurrence is an absolute must. For psychosis, the use of a LAI second-generation antipsychotic before hospital discharge from a first episode of psychosis can be disease-modifying, with a more benign illness trajectory and outcome than the devastating deterioration that follows repetitive psychotic relapse, most often due to nonadherence with oral medications.
Continue to: Psychosis should be conceptualized as...
Psychosis should be conceptualized as a “stroke of the mind,” and it can be prevented in most patients with schizophrenia by adopting injectable antipsychotics as early after the onset of psychosis as possible. Yet, starting a LAI antipsychotic drug in first-episode psychosis before hospital discharge is rarely done, and the few patients who currently receive LAIs (10% of U.S. patients) generally receive them after multiple episodes and a protracted DUP. That’s like calling the fire department when much of the house has turned to ashes, instead of calling them when the first small flame is noticed. It makes so much sense, but the decades-old practice of postponing the use of LAIs continues to ruin the lives of young persons in the prime of life. By changing our practice habits to early use of LAIs, we have nothing to lose and our patients with psychosis may be spared a lifetime of suffering, poverty, stigma, incarceration, and functional disability. Wouldn’t we want to avoid that atrocious outcome for our own family members if they develop schizophrenia?
1. Benjamin EJ, Virani SS, Callaway CW, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492.
2. Cechnicki A, Cichocki Ł, Kalisz A, et al. Duration of untreated psychosis (DUP) and the course of schizophrenia in a 20-year follow-up study. Psychiatry Res. 2014;219(3):420-425.
3. Davis J, Moylan S, Harvey BH, et al. Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014;48(6):512-529.
4. Olabi B, Ellison-Wright I, McIntosh AM, et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry. 2011;70(1):88-96.
5. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE Early Treatment Program. Am J Psychiatry. 2016;173(4):362-372.
6. Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015;161(1):102-112.
7. Nasrallah HA. For first-episode psychosis, psychiatrists should behave like cardiologists. Current Psychiatry. 2017;16(8):4-7.
8. Cahn W, Hulshoff Pol HE, Lems EB, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry. 2002;59(11):1002-1010.
9. McGorry P, Nelson B. Why we need a transdiagnostic staging approach to emerging psychopathology, early diagnosis, and treatment. JAMA Psychiatry. 2016;73(3):191-192.
10. Emsley R, Oosthuizen P, Koen L, et al. Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection. Int Clin Psychopharmacol. 2008;23(6):325-331.
11. Nasrallah HA. The crisis of poor physical health and early mortality of psychiatric patients. Current Psychiatry. 2018;17(4):7-8,11.
12. Nasrallah HA. Triple advantages of injectable long acting second generation antipsychotics: relapse prevention, neuroprotection, and lower mortality. Schizophr Res. 2018;197:69-70.
1. Benjamin EJ, Virani SS, Callaway CW, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492.
2. Cechnicki A, Cichocki Ł, Kalisz A, et al. Duration of untreated psychosis (DUP) and the course of schizophrenia in a 20-year follow-up study. Psychiatry Res. 2014;219(3):420-425.
3. Davis J, Moylan S, Harvey BH, et al. Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014;48(6):512-529.
4. Olabi B, Ellison-Wright I, McIntosh AM, et al. Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies. Biol Psychiatry. 2011;70(1):88-96.
5. Kane JM, Robinson DG, Schooler NR, et al. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE Early Treatment Program. Am J Psychiatry. 2016;173(4):362-372.
6. Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015;161(1):102-112.
7. Nasrallah HA. For first-episode psychosis, psychiatrists should behave like cardiologists. Current Psychiatry. 2017;16(8):4-7.
8. Cahn W, Hulshoff Pol HE, Lems EB, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry. 2002;59(11):1002-1010.
9. McGorry P, Nelson B. Why we need a transdiagnostic staging approach to emerging psychopathology, early diagnosis, and treatment. JAMA Psychiatry. 2016;73(3):191-192.
10. Emsley R, Oosthuizen P, Koen L, et al. Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection. Int Clin Psychopharmacol. 2008;23(6):325-331.
11. Nasrallah HA. The crisis of poor physical health and early mortality of psychiatric patients. Current Psychiatry. 2018;17(4):7-8,11.
12. Nasrallah HA. Triple advantages of injectable long acting second generation antipsychotics: relapse prevention, neuroprotection, and lower mortality. Schizophr Res. 2018;197:69-70.
Prophylactic haloperidol does not improve survival in critically ill patients
Clinical question: Does prophylactic use of haloperidol in critically ill patients at high risk of delirium improve survival at 28 days?
Background: Delirium occurs frequently in critically ill patients and can lead to increased ICU length of stay, hospital length of stay, duration of mechanical ventilation, and mortality. Prior research into the use of prophylactic antipsychotic administration has yielded inconsistent results.
Study design: Double-blind, randomized, controlled trial.
Setting: 21 ICUs in the Netherlands, from July 2013 to March 2017. 
Synopsis: A total of 1,789 critically ill adults with an anticipated ICU stay of at least 2 days were randomized to receive 1 mg of haloperidol, 2 mg of haloperidol, or a placebo three times daily. All study sites used “best practice” delirium prevention (for example, early mobilization, noise reduction, protocols aiming to prevent oversedation). The primary outcome was defined as the number of days patients survived in the 28 days following inclusion, and secondary outcome measures included number of days survived in 90 days, delirium incidence, number of delirium-free and coma-free days, duration of mechanical ventilation, and length of ICU and hospital stay. The 1-mg haloperidol group was stopped early because of futility. There was no significant difference between the 2-mg haloperidol group and the placebo group for the primary outcome (P = .93), or any of the secondary outcomes.Bottom line: In a population of critically ill patients at high risk of delirium, prophylactic haloperidol did not significantly improve 28-day survival, nor did it significantly reduce the incidence of delirium or length of stay.
Citation: van den Boogaard M et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018 Feb 20;319(7):680-90.
Dr. Winters is a hospitalist at Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, Boston.
Clinical question: Does prophylactic use of haloperidol in critically ill patients at high risk of delirium improve survival at 28 days?
Background: Delirium occurs frequently in critically ill patients and can lead to increased ICU length of stay, hospital length of stay, duration of mechanical ventilation, and mortality. Prior research into the use of prophylactic antipsychotic administration has yielded inconsistent results.
Study design: Double-blind, randomized, controlled trial.
Setting: 21 ICUs in the Netherlands, from July 2013 to March 2017.
Synopsis: A total of 1,789 critically ill adults with an anticipated ICU stay of at least 2 days were randomized to receive 1 mg of haloperidol, 2 mg of haloperidol, or a placebo three times daily. All study sites used “best practice” delirium prevention (for example, early mobilization, noise reduction, protocols aiming to prevent oversedation). The primary outcome was defined as the number of days patients survived in the 28 days following inclusion, and secondary outcome measures included number of days survived in 90 days, delirium incidence, number of delirium-free and coma-free days, duration of mechanical ventilation, and length of ICU and hospital stay. The 1-mg haloperidol group was stopped early because of futility. There was no significant difference between the 2-mg haloperidol group and the placebo group for the primary outcome (P = .93), or any of the secondary outcomes.Bottom line: In a population of critically ill patients at high risk of delirium, prophylactic haloperidol did not significantly improve 28-day survival, nor did it significantly reduce the incidence of delirium or length of stay.
Citation: van den Boogaard M et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018 Feb 20;319(7):680-90.
Dr. Winters is a hospitalist at Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, Boston.
Clinical question: Does prophylactic use of haloperidol in critically ill patients at high risk of delirium improve survival at 28 days?
Background: Delirium occurs frequently in critically ill patients and can lead to increased ICU length of stay, hospital length of stay, duration of mechanical ventilation, and mortality. Prior research into the use of prophylactic antipsychotic administration has yielded inconsistent results.
Study design: Double-blind, randomized, controlled trial.
Setting: 21 ICUs in the Netherlands, from July 2013 to March 2017.
Synopsis: A total of 1,789 critically ill adults with an anticipated ICU stay of at least 2 days were randomized to receive 1 mg of haloperidol, 2 mg of haloperidol, or a placebo three times daily. All study sites used “best practice” delirium prevention (for example, early mobilization, noise reduction, protocols aiming to prevent oversedation). The primary outcome was defined as the number of days patients survived in the 28 days following inclusion, and secondary outcome measures included number of days survived in 90 days, delirium incidence, number of delirium-free and coma-free days, duration of mechanical ventilation, and length of ICU and hospital stay. The 1-mg haloperidol group was stopped early because of futility. There was no significant difference between the 2-mg haloperidol group and the placebo group for the primary outcome (P = .93), or any of the secondary outcomes.Bottom line: In a population of critically ill patients at high risk of delirium, prophylactic haloperidol did not significantly improve 28-day survival, nor did it significantly reduce the incidence of delirium or length of stay.
Citation: van den Boogaard M et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA. 2018 Feb 20;319(7):680-90.
Dr. Winters is a hospitalist at Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, Boston.
Novel TKI PLX9486 showed efficacy against KIT mutations in GIST
CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.
Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.
One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.
“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.
“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.
The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.
They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”
The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.
The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.
In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.
The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.
At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.
“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.
SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.
Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.
One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.
“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.
“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.
The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.
They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”
The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.
The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.
In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.
The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.
At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.
“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.
SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
CHICAGO – A combination of the investigational agent PLX9486 with another novel tyrosine kinase inhibitor (TKI) showed some efficacy against a range of primary and secondary KIT mutations in patients with gastrointestinal stromal tumor (GIST), the results of a phase 1 dose escalation study have suggested.
Among 39 patients with GIST who had progressed on imatinib and other TKIs, the rates of clinical benefit at 16 weeks were 64% for 11 patients treated with PLX8486 monotherapy at a dose of 1,000 mg daily and 67% for 9 patients treated with PLX9486 and the investigational TKI pexidartinib.
One patient in the 1,000 mg monotherapy group had a partial response on interim analysis. The median progression-free survival in this dose group was 6 months, which was “significantly better than at lower doses,” reported Andrew J. Wagner, MD, PhD, from the Dana-Farber Cancer Institute in Boston and his colleagues.
“The combination of PLX9486 with either pexidartinib or sunitinib is generally well tolerated and toxicities are typically grade 1 or 2 in nature and reversible,” they wrote in a poster presented at the annual meeting of the American Society of Clinical Oncology.
PLX9486 is an inhibitor of KIT primary mutations in exons 9 and 11 and secondary resistance mutations in exons 17 and 18. Compared with other KIT-targeted TKIs, PLX9486 has complementary selectivity for mutant forms of KIT with a greater than 150-fold selectivity for mutant versus wild-type KIT, the investigators explained.
“Combinations of PLX9486 with either pexidartinib (PLX3397) or sunitinib potentially inhibit and address all common primary and secondary KIT mutations,” they wrote.
The investigators conducted a phase 1, open-label, dose-escalation study with two parts. The first part was designed to study the safety and pharmacokinetics of single-agent PLX9486 and established a maximum tolerated dose (MTD) for phase 2 studies. The second part was designed to study the drug as a single agent at the recommended phase 2 dose in GIST and other solid tumors with KIT mutations and also in combination with either pexidartinib or sunitinib in patients with GIST.
They found that single-agent PLX9486 was well tolerated at all doses tested (250, 300, 350, 500, and 1,000 mg daily) and that it selectively inhibited a spectrum of KIT mutations, “including difficult to treat exon 17/18 activation loop variants.”
The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67%, with a PFS on interim analysis of 6 months.
The efficacy of single agent PLX9486 was suggested by circulating tumor DNA studies, which showed reductions in circulating tumor DNA levels of exons 11 and 17/18, which reflected the selectivity profile of the TKI.
In the PLX9486 dose escalation phase, there were three cases of grade 3 or 4 toxicities, including one case each of fatigue, creatinine phosphokinase increase, and hypophosphatemia.
The combination of PLX9486 and pexidartinib was associated with grade 1 or 2 adverse events, including hair color changes in five patients; fatigue and decreased appetite in four patients each; anemia, diarrhea, nausea, alanine aminotransferase increase, and aspartate aminotransferase increase in three patients each; and weight loss, maculopapular rash, and hypertension in two patients each.
At the time of the poster presentation, the sunitinib cohort was still accruing, and interim efficacy data were not available.
“Given these interim results, it is anticipated that the selectivity profile and potency of PLX9486 + sunitinib combination will achieve broader and more durable coverage of primary and secondary KIT mutations,” Dr. Wagner and his associates wrote.
SOURCE: Wagner AJ et al. ASCO 2018, Abstract 11509.
PRESENTED AT ASCO 2018
Key clinical point: The novel tyrosine kinase inhibitor PLX9486 showed activity against resistance mutations in gastrointestinal stromal tumors.
Major finding: The combination of PLX9486 at 500 mg and pexidartinib 600 mg was associated with three partial responses and a clinical benefit rate of 67% with a PFS on interim analysis of 6 months.
Study details: Phase 1 dose-escalation, safety and pharmacokinetics study in 39 patients with GIST, four with adenocarcinomas, and one with follicular lymphoma.
Disclosures: The study was sponsored by Plexxikon. Dr. Wagner disclosed consulting or advisory roles with Prime Therapeutics, Lilly, and Loxo Oncology, as well as having received institutional research funding from AADi, Celldex Therapeutics, Daiichi Sankyo, Karyopharm Therapeutics, Lilly, and Plexxikon.
Source: Wagner AJ et al. ASCO 2018, Abstract 11509.