Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.

Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.

The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.

After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).

The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.

Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.

“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”

They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.

In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.

There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.

The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.

Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.

There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.

The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.

The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.

Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.

Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.

The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.

After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).

The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.

Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.

“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”

They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.

In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.

There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.

The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.

Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.

There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.

The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.

The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.

Treatment with checkpoint inhibitor pembrolizumab is associated with significant gains in overall survival among patients with treatment-refractory advanced urothelial carcinoma, according to new research.

Data from the KEYNOTE-045 trial was presented simultaneously at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, and published in the New England Journal of Medicine.

The open-label, international phase III trial involved 542 patients with advanced urothelial carcinoma that had recurred or progressed after platinum-based chemotherapy. Participants were randomized either to 200 mg pembrolizumab every 3 weeks, or the investigator’s choice of paclitaxel, docetaxel, or vinflunine chemotherapy.

After a median follow-up of 14.1 months, researchers saw a 27% lower hazard ratio for death among the pembrolizumab group, compared with the chemotherapy group (P = .002), with a median overall survival of 10.3 months with pembrolizumab, compared with 7.4 months with chemotherapy (N Engl J Med. 2017 Feb 17. doi: 10.1056/NEJMoa1613683).

The estimated overall survival rate at 1 year was 43.9% among those treated with pembrolizumab and 30.7% in the chemotherapy group. The authors also saw no significant differences when each chemotherapy regimen was examined separately.

Patients treated with pembrolizumab also showed a significant higher objective response rate, compared with those treated with chemotherapy (21.1% vs. 11.4%, P = .001). At the time of data cut-off, 72% of patients in the pembrolizumab group showed a continued response, compared with 35% of the chemotherapy group.

“Most responses in patients in the pembrolizumab group occurred quickly and were reported at the first scheduled imaging assessment,” wrote Joaquim Bellmunt, MD, PhD, from the Dana-Farber Cancer Institute, Boston and his coauthors. “Continued disease regression over time in some patients resulted in radiologically confirmed responses that were reported as long as 6.3 months after the start of therapy.”

They also looked at how the level of programmed death 1 ligand (PD-L1) expression in the tumor influenced response by examining outcomes in a subgroup of patients whose tumor PD-L1 combined positive score – the percentage of PD-L1 expressing tumor and infiltrating immune cells relative to the total number of tumor cells – exceeded 10%.

In this group, median overall survival was 8 months with pembrolizumab, compared with 5.2 months with chemotherapy, representing a significant 43% reduction in mortality with immunotherapy.

There was an interaction between smoking status and response, with current smokers showing a significantly greater response that favored pembrolizumab. The authors pointed out that this effect has also been observed in other advanced cancers, and may reflect the impact of a greater mutational load in the cancers of smokers.

The study did not find any difference in the duration of progression-free survival between the two groups, nor among participants with a PD-L1 combined positive score of 10% of more. Median progression-free survival was 2.1 months in the pembrolizumab group and 3.3 months in the chemotherapy group.

Researchers also noted a lower rate of adverse events among patients treated with pembrolizumab, compared with chemotherapy. Treatment-related adverse events of grade 3-5 occurred in 49.4% of patients on chemotherapy, compared with 15% of those on pembrolizumab.

There was one death from treatment-related pneumonitis in the pembrolizumab group, and three deaths attributed to the study treatment; one urinary tract obstruction, one malignant neoplasm, and one unspecified cause. In the chemotherapy group, there were two treatment-related deaths from sepsis, one from septic shock, and one unspecified.

The most common adverse events with chemotherapy were alopecia, fatigue, and anemia, while in the pembrolizumab group the most common side effects were pruritis, fatigue, and nausea.

The study was supported by Merck. Sixteen authors declared personal fees, grants, honoraria, consultancies, and advisory board positions with pharmaceutical companies including Merck, three authors were employees of Merck with stock options, and one had nothing to declare.

Older age and parity are established risk factors for pelvic organ prolapse, but the role of obesity has not been precisely determined. Results from a new meta-analysis show that overweight and obese women are significantly more likely to experience pelvic organ prolapse, compared with women of normal weight.

Researchers identified 22 published observational studies of varying design that evaluated pelvic organ prolapse (POP) and obesity. The studies enrolled 96,875 participants and logged 17,249 POP cases, of which 3,043 were considered clinically significant, and 2,359 cases that were classified as self-reported/symptomatic POP (Am J Obstet Gynecol. 2017 Feb 7. doi: 10.1016/j.ajog.2017.01.039)

Ayush Giri, PhD, of Vanderbilt University in Nashville, and his colleagues, found that overweight women (BMI of 25-30 kg/m²) had a risk ratio ranging from 1.36 to 1.40, compared with normal-weight women. For obese women (BMI of 30 kg/m² or greater) there was a risk ratio ranging from 1.47 to 1.61, compared with normal-weight women. The association between overweight and obesity and POP was stronger when the POP was clinically significant rather than self-reported and symptomatic.

The researchers called for more studies to prospectively evaluate the the association between obesity and POP.

In the meantime, they wrote, more can be done to educate women. “From a policy perspective, educating parous women about the association between obesity and POP, a common, yet less often talked about condition with debilitating effects on quality of life, may not only help reduce future burden of POP but may also help reduce obesity and related comorbidities in the population.”

The researchers reported having no conflicts of interest.

Older age and parity are established risk factors for pelvic organ prolapse, but the role of obesity has not been precisely determined. Results from a new meta-analysis show that overweight and obese women are significantly more likely to experience pelvic organ prolapse, compared with women of normal weight.

Researchers identified 22 published observational studies of varying design that evaluated pelvic organ prolapse (POP) and obesity. The studies enrolled 96,875 participants and logged 17,249 POP cases, of which 3,043 were considered clinically significant, and 2,359 cases that were classified as self-reported/symptomatic POP (Am J Obstet Gynecol. 2017 Feb 7. doi: 10.1016/j.ajog.2017.01.039)

Ayush Giri, PhD, of Vanderbilt University in Nashville, and his colleagues, found that overweight women (BMI of 25-30 kg/m²) had a risk ratio ranging from 1.36 to 1.40, compared with normal-weight women. For obese women (BMI of 30 kg/m² or greater) there was a risk ratio ranging from 1.47 to 1.61, compared with normal-weight women. The association between overweight and obesity and POP was stronger when the POP was clinically significant rather than self-reported and symptomatic.

The researchers called for more studies to prospectively evaluate the the association between obesity and POP.

In the meantime, they wrote, more can be done to educate women. “From a policy perspective, educating parous women about the association between obesity and POP, a common, yet less often talked about condition with debilitating effects on quality of life, may not only help reduce future burden of POP but may also help reduce obesity and related comorbidities in the population.”

The researchers reported having no conflicts of interest.

Older age and parity are established risk factors for pelvic organ prolapse, but the role of obesity has not been precisely determined. Results from a new meta-analysis show that overweight and obese women are significantly more likely to experience pelvic organ prolapse, compared with women of normal weight.

Researchers identified 22 published observational studies of varying design that evaluated pelvic organ prolapse (POP) and obesity. The studies enrolled 96,875 participants and logged 17,249 POP cases, of which 3,043 were considered clinically significant, and 2,359 cases that were classified as self-reported/symptomatic POP (Am J Obstet Gynecol. 2017 Feb 7. doi: 10.1016/j.ajog.2017.01.039)

Ayush Giri, PhD, of Vanderbilt University in Nashville, and his colleagues, found that overweight women (BMI of 25-30 kg/m²) had a risk ratio ranging from 1.36 to 1.40, compared with normal-weight women. For obese women (BMI of 30 kg/m² or greater) there was a risk ratio ranging from 1.47 to 1.61, compared with normal-weight women. The association between overweight and obesity and POP was stronger when the POP was clinically significant rather than self-reported and symptomatic.

The researchers called for more studies to prospectively evaluate the the association between obesity and POP.

In the meantime, they wrote, more can be done to educate women. “From a policy perspective, educating parous women about the association between obesity and POP, a common, yet less often talked about condition with debilitating effects on quality of life, may not only help reduce future burden of POP but may also help reduce obesity and related comorbidities in the population.”

The researchers reported having no conflicts of interest.

Advances in gene editing are pushing the possibility of raising pigs for organs that may be transplanted into humans with immunosuppression regimens comparable to those now used in human-to-human transplants, coauthors James Butler, MD, and A. Joseph Tector, MD, PhD, stated in an expert opinion in the February issue of the Journal of Thoracic and Cardiovascular Surgery (2017;153:488-92).

Developments in genome editing could bring new approaches to management of cardiopulmonary diseases, Dr. Butler and Dr. Tector noted. “Recently, cardiac-specific and lung-specific applications have been described, which will allow for the rapid creation of new models of heart and lung disease,” they said. Specifically, they noted gene targeting might eventually offer a way to treat challenging genetic problems “like the heterogeneous nature of nonsquamous cell lung cancer.”

Dr. Butler is with the department of surgery at Indiana University, Indianapolis, and Dr. Tector is with the department of surgery at the University of Alabama at Birmingham.

Agricultural Research Service/USDA

David Goodsell/Wikimedia Commons

Advances in gene editing are pushing the possibility of raising pigs for organs that may be transplanted into humans with immunosuppression regimens comparable to those now used in human-to-human transplants, coauthors James Butler, MD, and A. Joseph Tector, MD, PhD, stated in an expert opinion in the February issue of the Journal of Thoracic and Cardiovascular Surgery (2017;153:488-92).

Developments in genome editing could bring new approaches to management of cardiopulmonary diseases, Dr. Butler and Dr. Tector noted. “Recently, cardiac-specific and lung-specific applications have been described, which will allow for the rapid creation of new models of heart and lung disease,” they said. Specifically, they noted gene targeting might eventually offer a way to treat challenging genetic problems “like the heterogeneous nature of nonsquamous cell lung cancer.”

Dr. Butler is with the department of surgery at Indiana University, Indianapolis, and Dr. Tector is with the department of surgery at the University of Alabama at Birmingham.

Agricultural Research Service/USDA

David Goodsell/Wikimedia Commons

Advances in gene editing are pushing the possibility of raising pigs for organs that may be transplanted into humans with immunosuppression regimens comparable to those now used in human-to-human transplants, coauthors James Butler, MD, and A. Joseph Tector, MD, PhD, stated in an expert opinion in the February issue of the Journal of Thoracic and Cardiovascular Surgery (2017;153:488-92).

Developments in genome editing could bring new approaches to management of cardiopulmonary diseases, Dr. Butler and Dr. Tector noted. “Recently, cardiac-specific and lung-specific applications have been described, which will allow for the rapid creation of new models of heart and lung disease,” they said. Specifically, they noted gene targeting might eventually offer a way to treat challenging genetic problems “like the heterogeneous nature of nonsquamous cell lung cancer.”

Dr. Butler is with the department of surgery at Indiana University, Indianapolis, and Dr. Tector is with the department of surgery at the University of Alabama at Birmingham.

Agricultural Research Service/USDA

David Goodsell/Wikimedia Commons

ORLANDO – A genetic assay for prostate cancer typically used after radical prostatectomy could be used earlier, at the time of diagnostic biopsy testing, to classify patients as low, intermediate, and high risk for metastasis and disease-specific mortality, new research reveals.

Based on an approximately 1-mm biopsy sample, the Decipher Prostate Cancer Classifier assesses the activity of 22 genes relevant to prostate cancer. In a multicenter study of 175 patients, investigators found the 5-year risk for metastatic disease was 5.0% among patients classified as low risk by Decipher, 9.3% in the intermediate-risk group, and 23.4% in the high-risk patients.

Local Therapy for High-Risk Patients?

A meeting attendee asked if a patient is “known to be high risk on biopsy, and has a 23% chance of metastasis after treatment, why treat with local treatment in the first place?”

“For these patients, we’re meeting them up front and they have a high risk of disease, a 23% chance of metastasis, I think we’re going to throw everything we can at them,” Dr. Nguyen said. Multiple randomized controlled trials indicate intensifying therapy can improve outcomes and that local therapy contributes to overall survival in these patients, he added. “For these patients who have very high risk disease, we have enough randomized data to show local therapy is still important. The next thing we need to do is work on personalizing their systemic therapy, and figuring out how to integrate these novel systemic therapies based on their genomic scores.”

Disease-Specific Survival

Eleven participants in the study died from prostate cancer. The only variable associated with prostate-specific disease mortality was the Decipher classification, with a hazard ratio of 1.57 for every 10% increase in the score on a univariate model (P = .02).

Dr. Nguyen and his coinvestigators also assessed 5-year prostate cancer specific mortality. They found a 9.4% rate in the Decipher high-risk group, compared with 0% in both the intermediate- and low-risk groups.

“Okay, we have this data. How do we incorporate this test into our practices?” Dr. Nguyen asked. Because the low-risk patients only comprised 13% of the study population, he was unable to state that this group could be directed to active surveillance based on the findings.

What about NCCN intermediate risk? Should these people treated with dose-escalated radiation therapy also be given short-course hormone therapy? “So far we have not seen a survival improvement, and we’re awaiting a definitive trial,” Dr. Nguyen said.

Prognostic, Not Predictive

Could the high-risk classification help physicians decide among prostatectomy, radiation, and long-course hormone therapy versus enrolling patients in a clinical trial to test a novel agent? “Perhaps, and there is some rationale for thinking in that direction,” Dr. Nguyen said. “But it is important to understand the difference between a prognostic and predictive biomarker. We’ve shown Decipher has prognostic value for identifying patients at risk for distant metastases and death.” In contrast, randomized controlled trials would be required to identify a predictive marker that ultimately could guide choice of treatment in an individual, he said.

“Robust markers are needed to see who needs treatment, and which treatment is best for primary and metastatic prostate cancer,” said study discussant Angelo DeMarzo, MD, PhD, of Johns Hopkins University. He asked Dr. Nguyen about the next best step in his research.

“Our paper was mostly intermediate- and high-risk patients; I would personally love to learn more about which patients need long-course, short-course, or no hormone treatment,” Dr. Nguyen said. He would also like to conduct randomized trials to assess any role of Decipher classification for active surveillance, and for guiding treatment intensification versus de-escalation for those patients who receive therapy.

ORLANDO – A genetic assay for prostate cancer typically used after radical prostatectomy could be used earlier, at the time of diagnostic biopsy testing, to classify patients as low, intermediate, and high risk for metastasis and disease-specific mortality, new research reveals.

Based on an approximately 1-mm biopsy sample, the Decipher Prostate Cancer Classifier assesses the activity of 22 genes relevant to prostate cancer. In a multicenter study of 175 patients, investigators found the 5-year risk for metastatic disease was 5.0% among patients classified as low risk by Decipher, 9.3% in the intermediate-risk group, and 23.4% in the high-risk patients.

Local Therapy for High-Risk Patients?

A meeting attendee asked if a patient is “known to be high risk on biopsy, and has a 23% chance of metastasis after treatment, why treat with local treatment in the first place?”

“For these patients, we’re meeting them up front and they have a high risk of disease, a 23% chance of metastasis, I think we’re going to throw everything we can at them,” Dr. Nguyen said. Multiple randomized controlled trials indicate intensifying therapy can improve outcomes and that local therapy contributes to overall survival in these patients, he added. “For these patients who have very high risk disease, we have enough randomized data to show local therapy is still important. The next thing we need to do is work on personalizing their systemic therapy, and figuring out how to integrate these novel systemic therapies based on their genomic scores.”

Disease-Specific Survival

Eleven participants in the study died from prostate cancer. The only variable associated with prostate-specific disease mortality was the Decipher classification, with a hazard ratio of 1.57 for every 10% increase in the score on a univariate model (P = .02).

Dr. Nguyen and his coinvestigators also assessed 5-year prostate cancer specific mortality. They found a 9.4% rate in the Decipher high-risk group, compared with 0% in both the intermediate- and low-risk groups.

“Okay, we have this data. How do we incorporate this test into our practices?” Dr. Nguyen asked. Because the low-risk patients only comprised 13% of the study population, he was unable to state that this group could be directed to active surveillance based on the findings.

What about NCCN intermediate risk? Should these people treated with dose-escalated radiation therapy also be given short-course hormone therapy? “So far we have not seen a survival improvement, and we’re awaiting a definitive trial,” Dr. Nguyen said.

Prognostic, Not Predictive

Could the high-risk classification help physicians decide among prostatectomy, radiation, and long-course hormone therapy versus enrolling patients in a clinical trial to test a novel agent? “Perhaps, and there is some rationale for thinking in that direction,” Dr. Nguyen said. “But it is important to understand the difference between a prognostic and predictive biomarker. We’ve shown Decipher has prognostic value for identifying patients at risk for distant metastases and death.” In contrast, randomized controlled trials would be required to identify a predictive marker that ultimately could guide choice of treatment in an individual, he said.

“Robust markers are needed to see who needs treatment, and which treatment is best for primary and metastatic prostate cancer,” said study discussant Angelo DeMarzo, MD, PhD, of Johns Hopkins University. He asked Dr. Nguyen about the next best step in his research.

“Our paper was mostly intermediate- and high-risk patients; I would personally love to learn more about which patients need long-course, short-course, or no hormone treatment,” Dr. Nguyen said. He would also like to conduct randomized trials to assess any role of Decipher classification for active surveillance, and for guiding treatment intensification versus de-escalation for those patients who receive therapy.

ORLANDO – A genetic assay for prostate cancer typically used after radical prostatectomy could be used earlier, at the time of diagnostic biopsy testing, to classify patients as low, intermediate, and high risk for metastasis and disease-specific mortality, new research reveals.

Based on an approximately 1-mm biopsy sample, the Decipher Prostate Cancer Classifier assesses the activity of 22 genes relevant to prostate cancer. In a multicenter study of 175 patients, investigators found the 5-year risk for metastatic disease was 5.0% among patients classified as low risk by Decipher, 9.3% in the intermediate-risk group, and 23.4% in the high-risk patients.

Local Therapy for High-Risk Patients?

A meeting attendee asked if a patient is “known to be high risk on biopsy, and has a 23% chance of metastasis after treatment, why treat with local treatment in the first place?”

“For these patients, we’re meeting them up front and they have a high risk of disease, a 23% chance of metastasis, I think we’re going to throw everything we can at them,” Dr. Nguyen said. Multiple randomized controlled trials indicate intensifying therapy can improve outcomes and that local therapy contributes to overall survival in these patients, he added. “For these patients who have very high risk disease, we have enough randomized data to show local therapy is still important. The next thing we need to do is work on personalizing their systemic therapy, and figuring out how to integrate these novel systemic therapies based on their genomic scores.”

Disease-Specific Survival

Eleven participants in the study died from prostate cancer. The only variable associated with prostate-specific disease mortality was the Decipher classification, with a hazard ratio of 1.57 for every 10% increase in the score on a univariate model (P = .02).

Dr. Nguyen and his coinvestigators also assessed 5-year prostate cancer specific mortality. They found a 9.4% rate in the Decipher high-risk group, compared with 0% in both the intermediate- and low-risk groups.

“Okay, we have this data. How do we incorporate this test into our practices?” Dr. Nguyen asked. Because the low-risk patients only comprised 13% of the study population, he was unable to state that this group could be directed to active surveillance based on the findings.

What about NCCN intermediate risk? Should these people treated with dose-escalated radiation therapy also be given short-course hormone therapy? “So far we have not seen a survival improvement, and we’re awaiting a definitive trial,” Dr. Nguyen said.

Prognostic, Not Predictive

Could the high-risk classification help physicians decide among prostatectomy, radiation, and long-course hormone therapy versus enrolling patients in a clinical trial to test a novel agent? “Perhaps, and there is some rationale for thinking in that direction,” Dr. Nguyen said. “But it is important to understand the difference between a prognostic and predictive biomarker. We’ve shown Decipher has prognostic value for identifying patients at risk for distant metastases and death.” In contrast, randomized controlled trials would be required to identify a predictive marker that ultimately could guide choice of treatment in an individual, he said.

“Robust markers are needed to see who needs treatment, and which treatment is best for primary and metastatic prostate cancer,” said study discussant Angelo DeMarzo, MD, PhD, of Johns Hopkins University. He asked Dr. Nguyen about the next best step in his research.

“Our paper was mostly intermediate- and high-risk patients; I would personally love to learn more about which patients need long-course, short-course, or no hormone treatment,” Dr. Nguyen said. He would also like to conduct randomized trials to assess any role of Decipher classification for active surveillance, and for guiding treatment intensification versus de-escalation for those patients who receive therapy.

ORLANDO – A large analysis has identified 65 novel prostate cancer susceptibility loci, including an early-onset locus, and captured an additional 6% of the familial relevant risk for prostate cancer.

In the Oncoarray stratified analysis, the researchers detected two single nucleotide polymorphisms (SNPs) that were associated with early-onset prostate cancer, defined as disease occurring in men younger than 55 years, and four that were associated with both aggressive and indolent disease.

roobcio/Thinkstock

ORLANDO – A large analysis has identified 65 novel prostate cancer susceptibility loci, including an early-onset locus, and captured an additional 6% of the familial relevant risk for prostate cancer.

In the Oncoarray stratified analysis, the researchers detected two single nucleotide polymorphisms (SNPs) that were associated with early-onset prostate cancer, defined as disease occurring in men younger than 55 years, and four that were associated with both aggressive and indolent disease.

roobcio/Thinkstock

ORLANDO – A large analysis has identified 65 novel prostate cancer susceptibility loci, including an early-onset locus, and captured an additional 6% of the familial relevant risk for prostate cancer.

In the Oncoarray stratified analysis, the researchers detected two single nucleotide polymorphisms (SNPs) that were associated with early-onset prostate cancer, defined as disease occurring in men younger than 55 years, and four that were associated with both aggressive and indolent disease.

roobcio/Thinkstock

Researchers have identified a novel mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by bone marrow mesenchymal stem cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma leads directly to pro-malignancy signaling.

Specifically, increased PADI2 expression by bone marrow mesenchymal stem cells in patients with MGUS (a benign condition that precedes multiple myeloma) or with multiple myeloma directly induces upregulation of interleukin-6 expression through its enzymatic deimination of histone H3 arginine 26, which leads to acquired resistance to bortezomib – a “highly clinically relevant anti-myeloma drug”– by malignant plasma cells, Gavin McNee, PhD, of the University of Birmingham, England, and colleagues reported (Leukemia. 2017;31[2]:373-81).

The findings, based on transcriptomic analysis of mRNA extracted from bone marrow mesenchymal stem cells cultured from MGUS and multiple myeloma patients and controls, could have implications for therapeutic targeting of PADI2 in MGUS and multiple myeloma, the investigators said.

The findings, in the context of those from prior studies, “highlight the significant similarities between the microenvironment of the bone marrow in MGUS and multiple myeloma, suggesting that transformation of the bone marrow microenvironment is an early event in disease etiology, raising the potential of interfering with this process in order to delay or prevent progression of patients with MGUS to multiple myeloma,” they wrote, adding that the data “further highlight a need to identify those biological determinants in the [bone marrow] that actually contribute to the progression of this disease.”

The investigators concluded that PADI2 may therefore represent a good therapeutic target in MGUS and multiple myeloma patients, which “may act by removing a significant proportion of the supportive signaling required by malignant plasma cells for survival and proliferation.”

The authors were supported by grants from Bloodwise, Cancer Research UK, and the Medical Research Council, They reported having no other disclosures.

[email protected]

Researchers have identified a novel mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by bone marrow mesenchymal stem cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma leads directly to pro-malignancy signaling.

Specifically, increased PADI2 expression by bone marrow mesenchymal stem cells in patients with MGUS (a benign condition that precedes multiple myeloma) or with multiple myeloma directly induces upregulation of interleukin-6 expression through its enzymatic deimination of histone H3 arginine 26, which leads to acquired resistance to bortezomib – a “highly clinically relevant anti-myeloma drug”– by malignant plasma cells, Gavin McNee, PhD, of the University of Birmingham, England, and colleagues reported (Leukemia. 2017;31[2]:373-81).

The findings, based on transcriptomic analysis of mRNA extracted from bone marrow mesenchymal stem cells cultured from MGUS and multiple myeloma patients and controls, could have implications for therapeutic targeting of PADI2 in MGUS and multiple myeloma, the investigators said.

The findings, in the context of those from prior studies, “highlight the significant similarities between the microenvironment of the bone marrow in MGUS and multiple myeloma, suggesting that transformation of the bone marrow microenvironment is an early event in disease etiology, raising the potential of interfering with this process in order to delay or prevent progression of patients with MGUS to multiple myeloma,” they wrote, adding that the data “further highlight a need to identify those biological determinants in the [bone marrow] that actually contribute to the progression of this disease.”

The investigators concluded that PADI2 may therefore represent a good therapeutic target in MGUS and multiple myeloma patients, which “may act by removing a significant proportion of the supportive signaling required by malignant plasma cells for survival and proliferation.”

The authors were supported by grants from Bloodwise, Cancer Research UK, and the Medical Research Council, They reported having no other disclosures.

[email protected]

Researchers have identified a novel mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by bone marrow mesenchymal stem cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma leads directly to pro-malignancy signaling.

Specifically, increased PADI2 expression by bone marrow mesenchymal stem cells in patients with MGUS (a benign condition that precedes multiple myeloma) or with multiple myeloma directly induces upregulation of interleukin-6 expression through its enzymatic deimination of histone H3 arginine 26, which leads to acquired resistance to bortezomib – a “highly clinically relevant anti-myeloma drug”– by malignant plasma cells, Gavin McNee, PhD, of the University of Birmingham, England, and colleagues reported (Leukemia. 2017;31[2]:373-81).

The findings, based on transcriptomic analysis of mRNA extracted from bone marrow mesenchymal stem cells cultured from MGUS and multiple myeloma patients and controls, could have implications for therapeutic targeting of PADI2 in MGUS and multiple myeloma, the investigators said.

The findings, in the context of those from prior studies, “highlight the significant similarities between the microenvironment of the bone marrow in MGUS and multiple myeloma, suggesting that transformation of the bone marrow microenvironment is an early event in disease etiology, raising the potential of interfering with this process in order to delay or prevent progression of patients with MGUS to multiple myeloma,” they wrote, adding that the data “further highlight a need to identify those biological determinants in the [bone marrow] that actually contribute to the progression of this disease.”

The investigators concluded that PADI2 may therefore represent a good therapeutic target in MGUS and multiple myeloma patients, which “may act by removing a significant proportion of the supportive signaling required by malignant plasma cells for survival and proliferation.”

The authors were supported by grants from Bloodwise, Cancer Research UK, and the Medical Research Council, They reported having no other disclosures.

[email protected]

LAS VEGAS – Older obese patients shouldn’t be excluded from undergoing a Roux-en-Y gastric bypass based on concern for their long-term survival.

A 30-year review has determined that patients 60 years and older who had the surgery lost most of their excess body weight, and lived just as long as an age- and weight- matched cohort.

“We found a major weight loss benefit and no long-term differences in survival,” Taryn Hassinger, MD, said at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress. “Our data support the use of this surgery in the elderly to achieve safe and effective weight loss.”

• Obesity prevalence was higher among those aged 65-74, compared with those aged 75 and over in both men and women.

• The prevalence of obesity in women aged 65-74 was higher than in women aged 75 and over in all racial and ethnic groups except non-Hispanic black women, where approximately one in two were obese among both age groups.

• Between 1999-2002 and 2007-2010, the prevalence of obesity among older men increased.

As the proportion of older adults increases in the U.S. population, surgeons are likely to see older patients who are candidates for bariatric surgery, Dr. Hassinger said.

“We believe that surgery may be an option for people who are in the 60-70 year range,” she said. “We do operate on those patients not infrequently.”

The investigator had no disclosures.

[email protected]

On Twitter @Alz_Gal

LAS VEGAS – Older obese patients shouldn’t be excluded from undergoing a Roux-en-Y gastric bypass based on concern for their long-term survival.

A 30-year review has determined that patients 60 years and older who had the surgery lost most of their excess body weight, and lived just as long as an age- and weight- matched cohort.

“We found a major weight loss benefit and no long-term differences in survival,” Taryn Hassinger, MD, said at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress. “Our data support the use of this surgery in the elderly to achieve safe and effective weight loss.”

• Obesity prevalence was higher among those aged 65-74, compared with those aged 75 and over in both men and women.

• The prevalence of obesity in women aged 65-74 was higher than in women aged 75 and over in all racial and ethnic groups except non-Hispanic black women, where approximately one in two were obese among both age groups.

• Between 1999-2002 and 2007-2010, the prevalence of obesity among older men increased.

As the proportion of older adults increases in the U.S. population, surgeons are likely to see older patients who are candidates for bariatric surgery, Dr. Hassinger said.

“We believe that surgery may be an option for people who are in the 60-70 year range,” she said. “We do operate on those patients not infrequently.”

The investigator had no disclosures.

[email protected]

On Twitter @Alz_Gal

LAS VEGAS – Older obese patients shouldn’t be excluded from undergoing a Roux-en-Y gastric bypass based on concern for their long-term survival.

A 30-year review has determined that patients 60 years and older who had the surgery lost most of their excess body weight, and lived just as long as an age- and weight- matched cohort.

“We found a major weight loss benefit and no long-term differences in survival,” Taryn Hassinger, MD, said at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress. “Our data support the use of this surgery in the elderly to achieve safe and effective weight loss.”

• Obesity prevalence was higher among those aged 65-74, compared with those aged 75 and over in both men and women.

• The prevalence of obesity in women aged 65-74 was higher than in women aged 75 and over in all racial and ethnic groups except non-Hispanic black women, where approximately one in two were obese among both age groups.

• Between 1999-2002 and 2007-2010, the prevalence of obesity among older men increased.

As the proportion of older adults increases in the U.S. population, surgeons are likely to see older patients who are candidates for bariatric surgery, Dr. Hassinger said.

“We believe that surgery may be an option for people who are in the 60-70 year range,” she said. “We do operate on those patients not infrequently.”

The investigator had no disclosures.

[email protected]

On Twitter @Alz_Gal

Falls often result in injuries with devastating outcomes. In the elderly, falls are the largest cause of injury, mortality, and functional decline, leading to 40% of nursing home admissions.¹ Nationally, falls with injury are estimated to cost $19 billion in direct medical costs.² According to the National Quality Forum (NQF), hospital falls resulting in injury are reportable events. Beginning in fiscal year 2015, reportable events labeled as hospital acquired conditions (HAC) are subject to nonpayment, creating increased regulatory and reimbursement pressure on hospitals.³

Due to the major impact of a fall, The Joint Commission (TJC) requires hospitals to assess a patient’s fall risk on admission and whenever the patient’s condition changes.⁴ Despite decades of research evaluating various predictive strategies to identify individuals at fall risk, nutritional issues as interactive risk factors have received little attention.

A comparative study on the validity of fall risk assessment scales revealed that tools claiming to predict risk factors do not work well.⁵ Falls are the result of multiple interactive, synergistic pathologies and risk factors. In a multivariate regression study conducted by Lichtenstein and colleagues in Canada, lower body weight was found to be a statistically significant risk factor for falling.⁶ In 2004, Oliver and colleagues conducted a systematic review of fall risk assessment tools that included validation testing with sufficient data to allow for calculation of sensitivity, specificity, negative and positive predictive values, odds ratios, and confidence intervals.⁵

Fourteen studies identified common fall risk factors. The majority of these studies identified impaired cognition as a risk factor.⁵ Of the 14 studies included in the systematic analysis of Oliver and colleagues,^6-19 6 identified medications,^{6,8,11,12,17,18,} and 8 noted weakness and unsteady gait as risk factors.^{6,9-11,14,16,18,19} Only 1 study noted anemia as a risk factor for falls among patients who were post cerebral vascular accident.¹¹ Additionally, only 1 study noted an association between falls resulting in hip fracture and lower body weight.⁶

One in 4 adults admitted to a hospital is malnourished.^20,21 Components of malnutrition, including but not limited to anemia, clinically significant weight loss, and vitamin D deficiency, may be unrecognized interactive risk factors that increase the risk of hospital falls. Malnutrition and dehydration symptoms include fatigue, dizziness, irritability, loss of muscle mass, impulsivity, and the potential for poor judgment. Therefore, it is likely that the severity of specific malnutrition parameters is associated with recurrent falls and possibly injurious falls.

Hunger and inadequate food intake due to chronic disease or chronic food insecurity are real issues for the elderly. Insufficient caloric intake often leads to slow, progressive, and often unnoticed weight loss. The Academy of Nutrition and Dietetics (AND) and the American Association of Parenteral and Enteral Nutrition (ASPEN) have defined clinically significant weight loss categories to aid in the diagnosis of malnutrition. To aid in the diagnosis of various degrees of malnutrition, clinically significant weight loss is classified as ≥ 5% weight loss in 30 days; ≥ 7.5% weight loss in 90 days; > 10% in 180 days.²¹ The World Health Organization (WHO) identifies iron deficiency measured by hemoglobin (Hgb) value (for men < 13 g/dL) as the most common and widespread nutritional disorder in the world (Tables 1a, 1b, and 1c).²²

Eat Well, Fall Less is a retrospective chart review approved by the Louis Stokes Cleveland VAMC (LSCVAMC) Internal Review Board. The review seeks to determine whether degree of weight loss and decline in Hgb and vitamin D deficiency, factors of malnutrition, are present in recurrent fallers vs single-event fallers. Researchers hypothesized that individuals who experienced recurrent falls during hospitalization would demonstrate a greater degree of clinically significant weight loss compared with those who had experienced a single fall. The second hypothesis was that recurrent fallers also would have lower Hgb values than that of single-event fallers. The tertiary hypothesis was that individuals with a greater degree of vitamin D deficiency were more likely to be recurrent fallers compared with single-event fallers.

In addition, dementia has been previously identified as an independent risk factor for falls and recurrent falls.²³ During phase 2 of the study, the researchers hypothesized that in individuals with dementia, the concurrent diagnosis of malnutrition would be greatest in the recurrent fall population. A total of 30 subjects were included in the analysis.

Methods

Patient record search of note titles for falls was compiled daily. A random sample of 170 veterans who had experienced a fall was screened for study inclusion. Of the 170 charts, data from a total of 120 veterans who experienced a documented fall during a hospitalization between October 1, 2010 and October 31, 2012, were included in this analysis.

Eligibility Criteria and Baseline Characteristics

Chart reviews of veterans aged > 18 years experiencing a fall while hospitalized at the LSCVAMC between October 1, 2010 and October 31, 2012, were eligible to be included in this study. Each veteran needed to have 1 documented weight in a maximum of 24 months before the first fall and a minimum of 1 documented Hgb value prior to the first fall.

Patients were excluded if they had experienced a cerebrovascular accident or transient ischemic attack; a documented orthopedic fracture in the 12 months before the first fall; a documented amputation of a lower limb in the past 24 months; diagnosis of blindness; a lack of outpatient weight for greater than 24 months before the first fall; a history of volume overload, renal, cardiovascular, or other in nature during hospitalization; and alcoholism. Additionally, if any of the study investigators felt as though a patient had commorientes that made weight history inaccurate, those patients were excluded. Data were reviewed on 170 randomly selected subjects. A total of 50 subjects were excluded for not meeting the inclusion criteria; 120 individuals met eligible criteria. The patients who had experienced falls were divided into 2 groups: single-event fallers (1 fall documented during the study period) and recurrent fallers (2 or more falls documented during the study period). Fifty subjects were excluded from the final analysis because they met the following exclusion criteria: volume overload anytime in the 12 months before the documented fall (42); amputation of a lower limb before the fall (6); and prosthetic device alteration within the 12 months before the fall (3). One of the subjects was eliminated for both volume overload and amputation.

Data Collection

Data obtained from the Computerized Patient Record System review included age, gender, diagnosis, and body weight at the time of the first fall and 1 month, 3 months, 6 months, and 1 year before the first fall. Hemoglobin values at time of the first fall, 1 month, 3 months, 6 months, and 1 year before first documented fall also were collected. Vitamin D values and date of value also were collected. In year 2 of this multiphase retrospective review, charts again were reviewed and additional data collected, which included absence or presence of dementia along with type of dementia and the presence or absence of cancer. Year 2 data collection also included diagnosis of malnutrition by provider and registered dietitian assessment of degree of malnutrition.

Analysis

Data analysis comparing single-event fallers and frequent fallers was performed using IBM SPSS Statistic V22.0s. This pilot study has recognized weight loss and anemia as being associated with repeat falls. A 2-tailed t test was performed to evaluate differences in weight history, 25-hydroxyvitamin D, and Hgb characteristics between single fallers and frequent fallers. A repeated analysis of variance was performed to evaluate changes in weight and Hgb values over time for single and multiple falls. During phase 2 of this trial, a subanalysis comparing individuals with and without the diagnosis of dementia was conducted.

Results

The average age of the patients was 68 years. There was a significant decline in Hgb levels in both single-event fallers and frequent fallers at 12 and 6 months before the first fall event (95% confidence interval; P = .001). One year before the first fall, 28% of eventual fallers met WHO criteria for the diagnosis of mild anemia. One year before the first fall, none of the eventual fallers met WHO criteria for moderate or severe anemia. Using the lab data just before the first fall, 10% of fallers met WHO criteria for mild anemia, 48% met WHO criteria for moderate anemia, and 31% met WHO criteria for severe anemia. The degree of anemia in single-event fallers when compared with multiple-event fallers was insignificant. Interestingly, the degree of decline of Hgb value during the 6 months before the first fall event was notable for all fallers (Figure).

Only 60 of the 120 included patients had a documented vitamin D level. At the time of the fall, 46 patients had moderate vitamin D deficiency, and 23 patients had severe vitamin D deficiency, defined as < 32 mg/dL. The authors speculate that vitamin D status declines with malnutrition and increases fall risk.

Thirty participants were included in the dementia arm; 36.7% were single-event fallers, and 63.3% were multiple-event fallers (Table 2). The average age of the groups was 76.7 years and 73.9 years, respectively. Physician diagnosis of malnutrition was collected for both single- and multiple-event fallers. Of the single-event fallers with dementia, none had a diagnosis of malnutrition before the first hospital fall; and of the multiple-event fallers with dementia, all had a diagnosis of malnutrition before their first hospital fall. Individuals with a diagnosis of dementia and malnutrition fall frequently (P = .0028).

Discussion

In this study, falls occurred in a variety of patient populations. Both single-event fallers and recurrent fallers had a significant drop in Hgb values at 12, 6, and 3 months before the first fall. There was not a strong difference of the Hgb value between single-event falls and multiple fallers in the total population. Anemia was a significant risk factor for all fallers. The decline in the Hgb level before a fall is highly predictive of fall risk.

In individuals with dementia, those with the diagnosis of malnutrition are frequent fallers. A tool to assist in identification of this patient population along with a focused intervention strategy for this population is an area of needed research.

Further research is under way to determine which components of malnutrition diagnosis contribute to fall risk. If so, development of a fall assessment tool, including various components of malnutrition is warranted. Intervention strategies to reduce fall risk may soon include new nutrition and education techniques based on the faller constellation. Falls instruments that explore nutritional risk factors and falls should be investigated (ie, weight loss, vitamin D status, and anemia).

Falls occur in patients with a variety of risk factors (eg, mobility and cognition). The current screening instruments to assess fall risk factors do not sufficiently account for nutritional risk factors. In the Eat Well, Fall Less Study of hospitalized veterans, nutritional risk factors of anemia and weight loss also were associated with single- and multiple-event fallers. The AUTUMN falls instrument that includes critical elements of malnutrition, such as a decline in Hgb and weight loss, is currently being created and is in the process of being validated at LSCVAMC; this tool will incorporate components of malnutrition.

Acknowledgments
The authors acknowledge Michelle Pearson, Laura Guidotti, Adam Weier, Elizabeth Gable, and Shannon Corlett for their research contributions. In memory of Anne Raguso, RD, PhD, for her lifelong focus on nutrition research.

Falls often result in injuries with devastating outcomes. In the elderly, falls are the largest cause of injury, mortality, and functional decline, leading to 40% of nursing home admissions.¹ Nationally, falls with injury are estimated to cost $19 billion in direct medical costs.² According to the National Quality Forum (NQF), hospital falls resulting in injury are reportable events. Beginning in fiscal year 2015, reportable events labeled as hospital acquired conditions (HAC) are subject to nonpayment, creating increased regulatory and reimbursement pressure on hospitals.³

Due to the major impact of a fall, The Joint Commission (TJC) requires hospitals to assess a patient’s fall risk on admission and whenever the patient’s condition changes.⁴ Despite decades of research evaluating various predictive strategies to identify individuals at fall risk, nutritional issues as interactive risk factors have received little attention.

A comparative study on the validity of fall risk assessment scales revealed that tools claiming to predict risk factors do not work well.⁵ Falls are the result of multiple interactive, synergistic pathologies and risk factors. In a multivariate regression study conducted by Lichtenstein and colleagues in Canada, lower body weight was found to be a statistically significant risk factor for falling.⁶ In 2004, Oliver and colleagues conducted a systematic review of fall risk assessment tools that included validation testing with sufficient data to allow for calculation of sensitivity, specificity, negative and positive predictive values, odds ratios, and confidence intervals.⁵

Fourteen studies identified common fall risk factors. The majority of these studies identified impaired cognition as a risk factor.⁵ Of the 14 studies included in the systematic analysis of Oliver and colleagues,^6-19 6 identified medications,^{6,8,11,12,17,18,} and 8 noted weakness and unsteady gait as risk factors.^{6,9-11,14,16,18,19} Only 1 study noted anemia as a risk factor for falls among patients who were post cerebral vascular accident.¹¹ Additionally, only 1 study noted an association between falls resulting in hip fracture and lower body weight.⁶

One in 4 adults admitted to a hospital is malnourished.^20,21 Components of malnutrition, including but not limited to anemia, clinically significant weight loss, and vitamin D deficiency, may be unrecognized interactive risk factors that increase the risk of hospital falls. Malnutrition and dehydration symptoms include fatigue, dizziness, irritability, loss of muscle mass, impulsivity, and the potential for poor judgment. Therefore, it is likely that the severity of specific malnutrition parameters is associated with recurrent falls and possibly injurious falls.

Hunger and inadequate food intake due to chronic disease or chronic food insecurity are real issues for the elderly. Insufficient caloric intake often leads to slow, progressive, and often unnoticed weight loss. The Academy of Nutrition and Dietetics (AND) and the American Association of Parenteral and Enteral Nutrition (ASPEN) have defined clinically significant weight loss categories to aid in the diagnosis of malnutrition. To aid in the diagnosis of various degrees of malnutrition, clinically significant weight loss is classified as ≥ 5% weight loss in 30 days; ≥ 7.5% weight loss in 90 days; > 10% in 180 days.²¹ The World Health Organization (WHO) identifies iron deficiency measured by hemoglobin (Hgb) value (for men < 13 g/dL) as the most common and widespread nutritional disorder in the world (Tables 1a, 1b, and 1c).²²

Eat Well, Fall Less is a retrospective chart review approved by the Louis Stokes Cleveland VAMC (LSCVAMC) Internal Review Board. The review seeks to determine whether degree of weight loss and decline in Hgb and vitamin D deficiency, factors of malnutrition, are present in recurrent fallers vs single-event fallers. Researchers hypothesized that individuals who experienced recurrent falls during hospitalization would demonstrate a greater degree of clinically significant weight loss compared with those who had experienced a single fall. The second hypothesis was that recurrent fallers also would have lower Hgb values than that of single-event fallers. The tertiary hypothesis was that individuals with a greater degree of vitamin D deficiency were more likely to be recurrent fallers compared with single-event fallers.

In addition, dementia has been previously identified as an independent risk factor for falls and recurrent falls.²³ During phase 2 of the study, the researchers hypothesized that in individuals with dementia, the concurrent diagnosis of malnutrition would be greatest in the recurrent fall population. A total of 30 subjects were included in the analysis.

Methods

Patient record search of note titles for falls was compiled daily. A random sample of 170 veterans who had experienced a fall was screened for study inclusion. Of the 170 charts, data from a total of 120 veterans who experienced a documented fall during a hospitalization between October 1, 2010 and October 31, 2012, were included in this analysis.

Eligibility Criteria and Baseline Characteristics

Chart reviews of veterans aged > 18 years experiencing a fall while hospitalized at the LSCVAMC between October 1, 2010 and October 31, 2012, were eligible to be included in this study. Each veteran needed to have 1 documented weight in a maximum of 24 months before the first fall and a minimum of 1 documented Hgb value prior to the first fall.

Patients were excluded if they had experienced a cerebrovascular accident or transient ischemic attack; a documented orthopedic fracture in the 12 months before the first fall; a documented amputation of a lower limb in the past 24 months; diagnosis of blindness; a lack of outpatient weight for greater than 24 months before the first fall; a history of volume overload, renal, cardiovascular, or other in nature during hospitalization; and alcoholism. Additionally, if any of the study investigators felt as though a patient had commorientes that made weight history inaccurate, those patients were excluded. Data were reviewed on 170 randomly selected subjects. A total of 50 subjects were excluded for not meeting the inclusion criteria; 120 individuals met eligible criteria. The patients who had experienced falls were divided into 2 groups: single-event fallers (1 fall documented during the study period) and recurrent fallers (2 or more falls documented during the study period). Fifty subjects were excluded from the final analysis because they met the following exclusion criteria: volume overload anytime in the 12 months before the documented fall (42); amputation of a lower limb before the fall (6); and prosthetic device alteration within the 12 months before the fall (3). One of the subjects was eliminated for both volume overload and amputation.

Data Collection

Data obtained from the Computerized Patient Record System review included age, gender, diagnosis, and body weight at the time of the first fall and 1 month, 3 months, 6 months, and 1 year before the first fall. Hemoglobin values at time of the first fall, 1 month, 3 months, 6 months, and 1 year before first documented fall also were collected. Vitamin D values and date of value also were collected. In year 2 of this multiphase retrospective review, charts again were reviewed and additional data collected, which included absence or presence of dementia along with type of dementia and the presence or absence of cancer. Year 2 data collection also included diagnosis of malnutrition by provider and registered dietitian assessment of degree of malnutrition.

Analysis

Data analysis comparing single-event fallers and frequent fallers was performed using IBM SPSS Statistic V22.0s. This pilot study has recognized weight loss and anemia as being associated with repeat falls. A 2-tailed t test was performed to evaluate differences in weight history, 25-hydroxyvitamin D, and Hgb characteristics between single fallers and frequent fallers. A repeated analysis of variance was performed to evaluate changes in weight and Hgb values over time for single and multiple falls. During phase 2 of this trial, a subanalysis comparing individuals with and without the diagnosis of dementia was conducted.

Results

The average age of the patients was 68 years. There was a significant decline in Hgb levels in both single-event fallers and frequent fallers at 12 and 6 months before the first fall event (95% confidence interval; P = .001). One year before the first fall, 28% of eventual fallers met WHO criteria for the diagnosis of mild anemia. One year before the first fall, none of the eventual fallers met WHO criteria for moderate or severe anemia. Using the lab data just before the first fall, 10% of fallers met WHO criteria for mild anemia, 48% met WHO criteria for moderate anemia, and 31% met WHO criteria for severe anemia. The degree of anemia in single-event fallers when compared with multiple-event fallers was insignificant. Interestingly, the degree of decline of Hgb value during the 6 months before the first fall event was notable for all fallers (Figure).

Only 60 of the 120 included patients had a documented vitamin D level. At the time of the fall, 46 patients had moderate vitamin D deficiency, and 23 patients had severe vitamin D deficiency, defined as < 32 mg/dL. The authors speculate that vitamin D status declines with malnutrition and increases fall risk.

Thirty participants were included in the dementia arm; 36.7% were single-event fallers, and 63.3% were multiple-event fallers (Table 2). The average age of the groups was 76.7 years and 73.9 years, respectively. Physician diagnosis of malnutrition was collected for both single- and multiple-event fallers. Of the single-event fallers with dementia, none had a diagnosis of malnutrition before the first hospital fall; and of the multiple-event fallers with dementia, all had a diagnosis of malnutrition before their first hospital fall. Individuals with a diagnosis of dementia and malnutrition fall frequently (P = .0028).

Discussion

In this study, falls occurred in a variety of patient populations. Both single-event fallers and recurrent fallers had a significant drop in Hgb values at 12, 6, and 3 months before the first fall. There was not a strong difference of the Hgb value between single-event falls and multiple fallers in the total population. Anemia was a significant risk factor for all fallers. The decline in the Hgb level before a fall is highly predictive of fall risk.

In individuals with dementia, those with the diagnosis of malnutrition are frequent fallers. A tool to assist in identification of this patient population along with a focused intervention strategy for this population is an area of needed research.

Further research is under way to determine which components of malnutrition diagnosis contribute to fall risk. If so, development of a fall assessment tool, including various components of malnutrition is warranted. Intervention strategies to reduce fall risk may soon include new nutrition and education techniques based on the faller constellation. Falls instruments that explore nutritional risk factors and falls should be investigated (ie, weight loss, vitamin D status, and anemia).

Falls occur in patients with a variety of risk factors (eg, mobility and cognition). The current screening instruments to assess fall risk factors do not sufficiently account for nutritional risk factors. In the Eat Well, Fall Less Study of hospitalized veterans, nutritional risk factors of anemia and weight loss also were associated with single- and multiple-event fallers. The AUTUMN falls instrument that includes critical elements of malnutrition, such as a decline in Hgb and weight loss, is currently being created and is in the process of being validated at LSCVAMC; this tool will incorporate components of malnutrition.

Acknowledgments
The authors acknowledge Michelle Pearson, Laura Guidotti, Adam Weier, Elizabeth Gable, and Shannon Corlett for their research contributions. In memory of Anne Raguso, RD, PhD, for her lifelong focus on nutrition research.

Falls often result in injuries with devastating outcomes. In the elderly, falls are the largest cause of injury, mortality, and functional decline, leading to 40% of nursing home admissions.¹ Nationally, falls with injury are estimated to cost $19 billion in direct medical costs.² According to the National Quality Forum (NQF), hospital falls resulting in injury are reportable events. Beginning in fiscal year 2015, reportable events labeled as hospital acquired conditions (HAC) are subject to nonpayment, creating increased regulatory and reimbursement pressure on hospitals.³

Due to the major impact of a fall, The Joint Commission (TJC) requires hospitals to assess a patient’s fall risk on admission and whenever the patient’s condition changes.⁴ Despite decades of research evaluating various predictive strategies to identify individuals at fall risk, nutritional issues as interactive risk factors have received little attention.

A comparative study on the validity of fall risk assessment scales revealed that tools claiming to predict risk factors do not work well.⁵ Falls are the result of multiple interactive, synergistic pathologies and risk factors. In a multivariate regression study conducted by Lichtenstein and colleagues in Canada, lower body weight was found to be a statistically significant risk factor for falling.⁶ In 2004, Oliver and colleagues conducted a systematic review of fall risk assessment tools that included validation testing with sufficient data to allow for calculation of sensitivity, specificity, negative and positive predictive values, odds ratios, and confidence intervals.⁵

Fourteen studies identified common fall risk factors. The majority of these studies identified impaired cognition as a risk factor.⁵ Of the 14 studies included in the systematic analysis of Oliver and colleagues,^6-19 6 identified medications,^{6,8,11,12,17,18,} and 8 noted weakness and unsteady gait as risk factors.^{6,9-11,14,16,18,19} Only 1 study noted anemia as a risk factor for falls among patients who were post cerebral vascular accident.¹¹ Additionally, only 1 study noted an association between falls resulting in hip fracture and lower body weight.⁶

One in 4 adults admitted to a hospital is malnourished.^20,21 Components of malnutrition, including but not limited to anemia, clinically significant weight loss, and vitamin D deficiency, may be unrecognized interactive risk factors that increase the risk of hospital falls. Malnutrition and dehydration symptoms include fatigue, dizziness, irritability, loss of muscle mass, impulsivity, and the potential for poor judgment. Therefore, it is likely that the severity of specific malnutrition parameters is associated with recurrent falls and possibly injurious falls.

Hunger and inadequate food intake due to chronic disease or chronic food insecurity are real issues for the elderly. Insufficient caloric intake often leads to slow, progressive, and often unnoticed weight loss. The Academy of Nutrition and Dietetics (AND) and the American Association of Parenteral and Enteral Nutrition (ASPEN) have defined clinically significant weight loss categories to aid in the diagnosis of malnutrition. To aid in the diagnosis of various degrees of malnutrition, clinically significant weight loss is classified as ≥ 5% weight loss in 30 days; ≥ 7.5% weight loss in 90 days; > 10% in 180 days.²¹ The World Health Organization (WHO) identifies iron deficiency measured by hemoglobin (Hgb) value (for men < 13 g/dL) as the most common and widespread nutritional disorder in the world (Tables 1a, 1b, and 1c).²²

Eat Well, Fall Less is a retrospective chart review approved by the Louis Stokes Cleveland VAMC (LSCVAMC) Internal Review Board. The review seeks to determine whether degree of weight loss and decline in Hgb and vitamin D deficiency, factors of malnutrition, are present in recurrent fallers vs single-event fallers. Researchers hypothesized that individuals who experienced recurrent falls during hospitalization would demonstrate a greater degree of clinically significant weight loss compared with those who had experienced a single fall. The second hypothesis was that recurrent fallers also would have lower Hgb values than that of single-event fallers. The tertiary hypothesis was that individuals with a greater degree of vitamin D deficiency were more likely to be recurrent fallers compared with single-event fallers.

In addition, dementia has been previously identified as an independent risk factor for falls and recurrent falls.²³ During phase 2 of the study, the researchers hypothesized that in individuals with dementia, the concurrent diagnosis of malnutrition would be greatest in the recurrent fall population. A total of 30 subjects were included in the analysis.

Methods

Patient record search of note titles for falls was compiled daily. A random sample of 170 veterans who had experienced a fall was screened for study inclusion. Of the 170 charts, data from a total of 120 veterans who experienced a documented fall during a hospitalization between October 1, 2010 and October 31, 2012, were included in this analysis.

Eligibility Criteria and Baseline Characteristics

Chart reviews of veterans aged > 18 years experiencing a fall while hospitalized at the LSCVAMC between October 1, 2010 and October 31, 2012, were eligible to be included in this study. Each veteran needed to have 1 documented weight in a maximum of 24 months before the first fall and a minimum of 1 documented Hgb value prior to the first fall.

Patients were excluded if they had experienced a cerebrovascular accident or transient ischemic attack; a documented orthopedic fracture in the 12 months before the first fall; a documented amputation of a lower limb in the past 24 months; diagnosis of blindness; a lack of outpatient weight for greater than 24 months before the first fall; a history of volume overload, renal, cardiovascular, or other in nature during hospitalization; and alcoholism. Additionally, if any of the study investigators felt as though a patient had commorientes that made weight history inaccurate, those patients were excluded. Data were reviewed on 170 randomly selected subjects. A total of 50 subjects were excluded for not meeting the inclusion criteria; 120 individuals met eligible criteria. The patients who had experienced falls were divided into 2 groups: single-event fallers (1 fall documented during the study period) and recurrent fallers (2 or more falls documented during the study period). Fifty subjects were excluded from the final analysis because they met the following exclusion criteria: volume overload anytime in the 12 months before the documented fall (42); amputation of a lower limb before the fall (6); and prosthetic device alteration within the 12 months before the fall (3). One of the subjects was eliminated for both volume overload and amputation.

Data Collection

Data obtained from the Computerized Patient Record System review included age, gender, diagnosis, and body weight at the time of the first fall and 1 month, 3 months, 6 months, and 1 year before the first fall. Hemoglobin values at time of the first fall, 1 month, 3 months, 6 months, and 1 year before first documented fall also were collected. Vitamin D values and date of value also were collected. In year 2 of this multiphase retrospective review, charts again were reviewed and additional data collected, which included absence or presence of dementia along with type of dementia and the presence or absence of cancer. Year 2 data collection also included diagnosis of malnutrition by provider and registered dietitian assessment of degree of malnutrition.

Analysis

Data analysis comparing single-event fallers and frequent fallers was performed using IBM SPSS Statistic V22.0s. This pilot study has recognized weight loss and anemia as being associated with repeat falls. A 2-tailed t test was performed to evaluate differences in weight history, 25-hydroxyvitamin D, and Hgb characteristics between single fallers and frequent fallers. A repeated analysis of variance was performed to evaluate changes in weight and Hgb values over time for single and multiple falls. During phase 2 of this trial, a subanalysis comparing individuals with and without the diagnosis of dementia was conducted.

Results

The average age of the patients was 68 years. There was a significant decline in Hgb levels in both single-event fallers and frequent fallers at 12 and 6 months before the first fall event (95% confidence interval; P = .001). One year before the first fall, 28% of eventual fallers met WHO criteria for the diagnosis of mild anemia. One year before the first fall, none of the eventual fallers met WHO criteria for moderate or severe anemia. Using the lab data just before the first fall, 10% of fallers met WHO criteria for mild anemia, 48% met WHO criteria for moderate anemia, and 31% met WHO criteria for severe anemia. The degree of anemia in single-event fallers when compared with multiple-event fallers was insignificant. Interestingly, the degree of decline of Hgb value during the 6 months before the first fall event was notable for all fallers (Figure).

Only 60 of the 120 included patients had a documented vitamin D level. At the time of the fall, 46 patients had moderate vitamin D deficiency, and 23 patients had severe vitamin D deficiency, defined as < 32 mg/dL. The authors speculate that vitamin D status declines with malnutrition and increases fall risk.

Thirty participants were included in the dementia arm; 36.7% were single-event fallers, and 63.3% were multiple-event fallers (Table 2). The average age of the groups was 76.7 years and 73.9 years, respectively. Physician diagnosis of malnutrition was collected for both single- and multiple-event fallers. Of the single-event fallers with dementia, none had a diagnosis of malnutrition before the first hospital fall; and of the multiple-event fallers with dementia, all had a diagnosis of malnutrition before their first hospital fall. Individuals with a diagnosis of dementia and malnutrition fall frequently (P = .0028).

Discussion

In this study, falls occurred in a variety of patient populations. Both single-event fallers and recurrent fallers had a significant drop in Hgb values at 12, 6, and 3 months before the first fall. There was not a strong difference of the Hgb value between single-event falls and multiple fallers in the total population. Anemia was a significant risk factor for all fallers. The decline in the Hgb level before a fall is highly predictive of fall risk.

In individuals with dementia, those with the diagnosis of malnutrition are frequent fallers. A tool to assist in identification of this patient population along with a focused intervention strategy for this population is an area of needed research.

Further research is under way to determine which components of malnutrition diagnosis contribute to fall risk. If so, development of a fall assessment tool, including various components of malnutrition is warranted. Intervention strategies to reduce fall risk may soon include new nutrition and education techniques based on the faller constellation. Falls instruments that explore nutritional risk factors and falls should be investigated (ie, weight loss, vitamin D status, and anemia).

Falls occur in patients with a variety of risk factors (eg, mobility and cognition). The current screening instruments to assess fall risk factors do not sufficiently account for nutritional risk factors. In the Eat Well, Fall Less Study of hospitalized veterans, nutritional risk factors of anemia and weight loss also were associated with single- and multiple-event fallers. The AUTUMN falls instrument that includes critical elements of malnutrition, such as a decline in Hgb and weight loss, is currently being created and is in the process of being validated at LSCVAMC; this tool will incorporate components of malnutrition.

Acknowledgments
The authors acknowledge Michelle Pearson, Laura Guidotti, Adam Weier, Elizabeth Gable, and Shannon Corlett for their research contributions. In memory of Anne Raguso, RD, PhD, for her lifelong focus on nutrition research.

Photo courtesy of CDC

Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.

The team found they could accurately identify those TKIs already known to be the most dangerous.

The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.

“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.

“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”

Dr Wu and his colleagues described this research in Science Translational Medicine.

The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.

The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.

Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.

The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.

High cardiotoxicity

Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.

These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.

Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.

The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.

This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.

They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.

“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”

Photo courtesy of CDC

Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.

The team found they could accurately identify those TKIs already known to be the most dangerous.

The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.

“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.

“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”

Dr Wu and his colleagues described this research in Science Translational Medicine.

The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.

The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.

Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.

The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.

High cardiotoxicity

Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.

These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.

Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.

The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.

This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.

They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.

“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”

Photo courtesy of CDC

Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.

The team found they could accurately identify those TKIs already known to be the most dangerous.

The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.

“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.

“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”

Dr Wu and his colleagues described this research in Science Translational Medicine.

The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.

The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.

Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.

The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.

High cardiotoxicity

Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.

These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.

Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.

The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.

This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.

They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.

“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”