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Influenza activity continues to be unusually high
The 2019-2020 flu season continues its unusually early rise in activity, with the Centers for Disease Control and Prevention estimating that 3.7 million cases have occurred through Dec. 14.
which is up from 3.2% the previous week and is the sixth consecutive week that the United States has been at or above the national baseline of 2.4%, the CDC reported Dec. 20. This year’s 3.9% is the highest mid-December rate recorded since 2003, when it reached almost 7.4%.
Most of the influenza activity so far this season is being driven by influenza B/Victoria viruses. Nationwide testing puts influenza B prevalence at 68.5% of all positive specimens, exactly the same as last week, but A(H1N1) viruses “are increasing in proportion relative to other influenza viruses in some regions,” the CDC’s influenza division said.
A look at this week’s activity map shows that 21 states, compared with 12 last week, were in the “high” range of activity – that’s levels 8-10 on the CDC’s 1-10 scale. Twelve of those states, along with Puerto Rico, were at level 10, which was up from nine a week earlier, the CDC said.
The overall hospitalization rate through the week of Dec. 8-14 (5.5 per 100,000 population) “is similar to what has been seen at this time during recent seasons,” the CDC noted. The highest rates are occurring among adults over age 65 years (12.7 per 100,000) and children aged 0-4 years (10.9 per 100,000).
Three ILI-related deaths among children that occurred last week were reported, which brings the total for the 2019-2020 season to 19, the CDC said.
The 2019-2020 flu season continues its unusually early rise in activity, with the Centers for Disease Control and Prevention estimating that 3.7 million cases have occurred through Dec. 14.
which is up from 3.2% the previous week and is the sixth consecutive week that the United States has been at or above the national baseline of 2.4%, the CDC reported Dec. 20. This year’s 3.9% is the highest mid-December rate recorded since 2003, when it reached almost 7.4%.
Most of the influenza activity so far this season is being driven by influenza B/Victoria viruses. Nationwide testing puts influenza B prevalence at 68.5% of all positive specimens, exactly the same as last week, but A(H1N1) viruses “are increasing in proportion relative to other influenza viruses in some regions,” the CDC’s influenza division said.
A look at this week’s activity map shows that 21 states, compared with 12 last week, were in the “high” range of activity – that’s levels 8-10 on the CDC’s 1-10 scale. Twelve of those states, along with Puerto Rico, were at level 10, which was up from nine a week earlier, the CDC said.
The overall hospitalization rate through the week of Dec. 8-14 (5.5 per 100,000 population) “is similar to what has been seen at this time during recent seasons,” the CDC noted. The highest rates are occurring among adults over age 65 years (12.7 per 100,000) and children aged 0-4 years (10.9 per 100,000).
Three ILI-related deaths among children that occurred last week were reported, which brings the total for the 2019-2020 season to 19, the CDC said.
The 2019-2020 flu season continues its unusually early rise in activity, with the Centers for Disease Control and Prevention estimating that 3.7 million cases have occurred through Dec. 14.
which is up from 3.2% the previous week and is the sixth consecutive week that the United States has been at or above the national baseline of 2.4%, the CDC reported Dec. 20. This year’s 3.9% is the highest mid-December rate recorded since 2003, when it reached almost 7.4%.
Most of the influenza activity so far this season is being driven by influenza B/Victoria viruses. Nationwide testing puts influenza B prevalence at 68.5% of all positive specimens, exactly the same as last week, but A(H1N1) viruses “are increasing in proportion relative to other influenza viruses in some regions,” the CDC’s influenza division said.
A look at this week’s activity map shows that 21 states, compared with 12 last week, were in the “high” range of activity – that’s levels 8-10 on the CDC’s 1-10 scale. Twelve of those states, along with Puerto Rico, were at level 10, which was up from nine a week earlier, the CDC said.
The overall hospitalization rate through the week of Dec. 8-14 (5.5 per 100,000 population) “is similar to what has been seen at this time during recent seasons,” the CDC noted. The highest rates are occurring among adults over age 65 years (12.7 per 100,000) and children aged 0-4 years (10.9 per 100,000).
Three ILI-related deaths among children that occurred last week were reported, which brings the total for the 2019-2020 season to 19, the CDC said.
LOXO-305: Next-gen BTK inhibitor safe and effective in B-cell malignancies
ORLANDO – A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax, according to an investigator.
The antitumor activity of this highly selective investigational oral BTK inhibitor was significant in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with a rapid onset of action and resolution of lymphocytosis “consistent with effective BTK target inhibition,” said Anthony R. Mato, MD, of the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
Responses were also seen in patients with BTK C481 mutations, the primary cause of progressive CLL after BTK inhibitor use, Dr. Mato said at the annual meeting of the American Society of Hematology.
The safety and tolerability profile of LOXO-305 is “consistent with highly selective drug design,” with no evidence of off-target effects, he said. “Collectively, these data demonstrate that BTK remains a highly actionable target despite progression on covalent BTK inhibitors.”
While BTK inhibitors have transformed treatment of B-cell malignancies, resistance remains a major problem, said Dr. Mato, citing 5-year ibrutinib discontinuation rates of 41% in the front line setting and 53.7% in the relapsed/refractory setting.
Key reasons for discontinuation are intolerance, events such as atrial fibrillation and major bleeding, progression of disease, and the appearance of BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition, he said. In contrast, LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status.
Dr. Mato described results of the phase 1 BRUIN trial, in which 28 adult patients with CLL or B-cell non-Hodgkin lymphomas received once daily oral LOXO-305 at doses ranging from 25 mg to 200 mg. All patients had received at least two lines of prior therapy and had active disease in need of treatment.
For 13 evaluable CLL patients, the overall response rate was 77% (10 patients), Dr. Mato reported. Overall response rates for MCL and other B-cell malignancies were 50%, or three out of six MCL patients and two of four patients with Waldenström macroglobulinemia, diffuse large B-cell lymphoma, or marginal zone lymphoma.
Though only a small subset of CLL patients have had multiple response assessments, the available data suggest that responses “deepen over time” with continued LOXO-305 treatment, Dr. Mato said.
With the median follow-up of 2.7 months, 24 of 28 patients remain on therapy, including all responders. “Some of the responses appear to be quite durable,” Dr. Mato said.
There have been no dose-limiting toxicities, the maximum tolerated dose has not been reached, and there have been no notable adverse events characteristic of covalent BTK inhibitors – namely atrial fibrillation or major bleeding – despite frequent monitoring, according to Dr. Mato.
There were two grade 3 events (leukocytosis and neutropenia), but the remaining treatment-emergent adverse events have been grade 1-2. “Having managed many of these patients, I can tell you that these adverse events were quite manageable,” Dr. Mato told attendees.
BRUIN is a global trial that continues to enroll patients at 18 sites in 3 countries, with a plan in 2020 to incorporate “rational combinations” of agents, according to the investigator.
Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 501.
ORLANDO – A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax, according to an investigator.
The antitumor activity of this highly selective investigational oral BTK inhibitor was significant in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with a rapid onset of action and resolution of lymphocytosis “consistent with effective BTK target inhibition,” said Anthony R. Mato, MD, of the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
Responses were also seen in patients with BTK C481 mutations, the primary cause of progressive CLL after BTK inhibitor use, Dr. Mato said at the annual meeting of the American Society of Hematology.
The safety and tolerability profile of LOXO-305 is “consistent with highly selective drug design,” with no evidence of off-target effects, he said. “Collectively, these data demonstrate that BTK remains a highly actionable target despite progression on covalent BTK inhibitors.”
While BTK inhibitors have transformed treatment of B-cell malignancies, resistance remains a major problem, said Dr. Mato, citing 5-year ibrutinib discontinuation rates of 41% in the front line setting and 53.7% in the relapsed/refractory setting.
Key reasons for discontinuation are intolerance, events such as atrial fibrillation and major bleeding, progression of disease, and the appearance of BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition, he said. In contrast, LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status.
Dr. Mato described results of the phase 1 BRUIN trial, in which 28 adult patients with CLL or B-cell non-Hodgkin lymphomas received once daily oral LOXO-305 at doses ranging from 25 mg to 200 mg. All patients had received at least two lines of prior therapy and had active disease in need of treatment.
For 13 evaluable CLL patients, the overall response rate was 77% (10 patients), Dr. Mato reported. Overall response rates for MCL and other B-cell malignancies were 50%, or three out of six MCL patients and two of four patients with Waldenström macroglobulinemia, diffuse large B-cell lymphoma, or marginal zone lymphoma.
Though only a small subset of CLL patients have had multiple response assessments, the available data suggest that responses “deepen over time” with continued LOXO-305 treatment, Dr. Mato said.
With the median follow-up of 2.7 months, 24 of 28 patients remain on therapy, including all responders. “Some of the responses appear to be quite durable,” Dr. Mato said.
There have been no dose-limiting toxicities, the maximum tolerated dose has not been reached, and there have been no notable adverse events characteristic of covalent BTK inhibitors – namely atrial fibrillation or major bleeding – despite frequent monitoring, according to Dr. Mato.
There were two grade 3 events (leukocytosis and neutropenia), but the remaining treatment-emergent adverse events have been grade 1-2. “Having managed many of these patients, I can tell you that these adverse events were quite manageable,” Dr. Mato told attendees.
BRUIN is a global trial that continues to enroll patients at 18 sites in 3 countries, with a plan in 2020 to incorporate “rational combinations” of agents, according to the investigator.
Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 501.
ORLANDO – A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax, according to an investigator.
The antitumor activity of this highly selective investigational oral BTK inhibitor was significant in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with a rapid onset of action and resolution of lymphocytosis “consistent with effective BTK target inhibition,” said Anthony R. Mato, MD, of the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
Responses were also seen in patients with BTK C481 mutations, the primary cause of progressive CLL after BTK inhibitor use, Dr. Mato said at the annual meeting of the American Society of Hematology.
The safety and tolerability profile of LOXO-305 is “consistent with highly selective drug design,” with no evidence of off-target effects, he said. “Collectively, these data demonstrate that BTK remains a highly actionable target despite progression on covalent BTK inhibitors.”
While BTK inhibitors have transformed treatment of B-cell malignancies, resistance remains a major problem, said Dr. Mato, citing 5-year ibrutinib discontinuation rates of 41% in the front line setting and 53.7% in the relapsed/refractory setting.
Key reasons for discontinuation are intolerance, events such as atrial fibrillation and major bleeding, progression of disease, and the appearance of BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition, he said. In contrast, LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status.
Dr. Mato described results of the phase 1 BRUIN trial, in which 28 adult patients with CLL or B-cell non-Hodgkin lymphomas received once daily oral LOXO-305 at doses ranging from 25 mg to 200 mg. All patients had received at least two lines of prior therapy and had active disease in need of treatment.
For 13 evaluable CLL patients, the overall response rate was 77% (10 patients), Dr. Mato reported. Overall response rates for MCL and other B-cell malignancies were 50%, or three out of six MCL patients and two of four patients with Waldenström macroglobulinemia, diffuse large B-cell lymphoma, or marginal zone lymphoma.
Though only a small subset of CLL patients have had multiple response assessments, the available data suggest that responses “deepen over time” with continued LOXO-305 treatment, Dr. Mato said.
With the median follow-up of 2.7 months, 24 of 28 patients remain on therapy, including all responders. “Some of the responses appear to be quite durable,” Dr. Mato said.
There have been no dose-limiting toxicities, the maximum tolerated dose has not been reached, and there have been no notable adverse events characteristic of covalent BTK inhibitors – namely atrial fibrillation or major bleeding – despite frequent monitoring, according to Dr. Mato.
There were two grade 3 events (leukocytosis and neutropenia), but the remaining treatment-emergent adverse events have been grade 1-2. “Having managed many of these patients, I can tell you that these adverse events were quite manageable,” Dr. Mato told attendees.
BRUIN is a global trial that continues to enroll patients at 18 sites in 3 countries, with a plan in 2020 to incorporate “rational combinations” of agents, according to the investigator.
Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract 501.
REPORTING FROM ASH 2019
First autoimmune epilepsy RCT supports IVIG therapy
BALTIMORE –
Although the numbers of enrolled subjects was small, it was the first double-blind, placebo-controlled randomized trial in autoimmune epilepsy, the start of a level 1 evidence base. Until now, treatment has been based mostly on case reports and expert opinion. “We’ve clearly shown that immunotherapy works and that treating early makes a difference, much more so than antiseizure medications,” said lead author Divyanshu Dubey, MBBS, from the Mayo Clinic.
The lack of data has meant that “we couldn’t get insurance approval for IVIG, so people have generally leaned towards” high-dose intravenous steroids, which are problematic because LGI-1 antibody epilepsy is a disease of older people, in whom osteoporosis, underlying infections, and other problems complicate steroid use, Dr. Dubey said.
The trial also included three people with contactin-associated-protein-like-2 (CASPR2) antibody epilepsy, but they all wound up in the placebo arm, “so it’s hard to say anything about them,” Dr. Dubey said at the American Epilepsy Society annual meeting. The work was published shortly before the meeting (Ann Neurol. 2019 Nov 28. doi: 10.1002/ana.25655).
CASPR2 and LGI-1 are proteins found in brain cells; attack by antibodies triggers encephalitis and tens to hundreds of seizures per day. The seizures tend to diminish with time, but the cognitive damage caused by the encephalitis does not. “We’ve seen patients end up in nursing homes diagnosed with Alzheimer’s disease” because the conditions weren’t recognized and treated, Dr. Dubey said.
He and his team chose LGI-1 and CASPR2 epilepsy because of the potentially devastating consequences and because they are among the most common autoimmune epilepsies for which antibodies have been identified. There was also a hope that positive results might open up insurance coverage.
The trial randomized eight people to IVIG 0.5 g/kg on day 1; 1 g/kg on day 2; and 0.6 g/kg once at 3 and 5 weeks. Nine others were randomized to volume-matched IV saline placebo on the same schedule. After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated because of slow enrollment.
Although none of the LGI-1 subjects in the placebo group responded, two CASPR2 patients did, yielding an IVIG response rate of 75% versus 22% (2/9) in the placebo arm after week 5 (odds ratio, 10.5; 95% confidence interval, 1.1-98.9; P = .044).
Two of the LGI-1 subjects in the IVIG arm were completely seizure free after treatment. Results in both arms, meanwhile, did not correlate with concomitant antiseizure medications among those who were on them.
All eight IVIG patients showed stabilization or improvement in cognitive function, compared with two of five in the placebo arm, as gauged by Repeatable Battery for the Assessment of Neuropsychological Status scores. Patients in the IVIG arm gained a median of 3 points, while patients in the placebo arm lost a median of 1 point (P = .077).
At week 5, six patients with persistent seizures who were in the placebo group were switched to the IVIG regimen after unblinding; four (67%) reported more than a 50% reduction in seizures.
Responses did not correlate with LGI-1/CASPR2-IgG1-4 subclass, and there were no IVIG-associated adverse events. One IVIG patients fell because of a faciobrachial dystonic seizure, a classic sign of LGI-1 disease. Antibodies were not measured in the trial because they “do not correlate with severity of autoimmune epilepsy,” Dr. Dubey said.
The original plan was to enroll 30 subjects, but the investigators terminated the study after 18 because of slow enrollment. With knowledge of autoimmune epilepsy growing at Mayo, it was increasingly difficult to find immunotherapy-naive patients, he said.
All the subjects were between 60 and 70 years old, and the majority in both arms were men, which was not surprising because the conditions skew male, Dr. Dubey said. None of the patients had underlying tumors, which are known triggers of autoimmune epilepsy.
This work was funded by Grifols Shared Services, a maker of IVIG, and Option Care, a provider of home infusion equipment. Dr. Dubey said the company had no active role in the trial, but that the lack of insurance coverage for IVIG in autoimmune epilepsy was one of the drivers of the study. He disclosed research support from Grifols; another investigator is a consultant.
SOURCE: Dubey D et al. AES 2019, Abstract 1.292.
BALTIMORE –
Although the numbers of enrolled subjects was small, it was the first double-blind, placebo-controlled randomized trial in autoimmune epilepsy, the start of a level 1 evidence base. Until now, treatment has been based mostly on case reports and expert opinion. “We’ve clearly shown that immunotherapy works and that treating early makes a difference, much more so than antiseizure medications,” said lead author Divyanshu Dubey, MBBS, from the Mayo Clinic.
The lack of data has meant that “we couldn’t get insurance approval for IVIG, so people have generally leaned towards” high-dose intravenous steroids, which are problematic because LGI-1 antibody epilepsy is a disease of older people, in whom osteoporosis, underlying infections, and other problems complicate steroid use, Dr. Dubey said.
The trial also included three people with contactin-associated-protein-like-2 (CASPR2) antibody epilepsy, but they all wound up in the placebo arm, “so it’s hard to say anything about them,” Dr. Dubey said at the American Epilepsy Society annual meeting. The work was published shortly before the meeting (Ann Neurol. 2019 Nov 28. doi: 10.1002/ana.25655).
CASPR2 and LGI-1 are proteins found in brain cells; attack by antibodies triggers encephalitis and tens to hundreds of seizures per day. The seizures tend to diminish with time, but the cognitive damage caused by the encephalitis does not. “We’ve seen patients end up in nursing homes diagnosed with Alzheimer’s disease” because the conditions weren’t recognized and treated, Dr. Dubey said.
He and his team chose LGI-1 and CASPR2 epilepsy because of the potentially devastating consequences and because they are among the most common autoimmune epilepsies for which antibodies have been identified. There was also a hope that positive results might open up insurance coverage.
The trial randomized eight people to IVIG 0.5 g/kg on day 1; 1 g/kg on day 2; and 0.6 g/kg once at 3 and 5 weeks. Nine others were randomized to volume-matched IV saline placebo on the same schedule. After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated because of slow enrollment.
Although none of the LGI-1 subjects in the placebo group responded, two CASPR2 patients did, yielding an IVIG response rate of 75% versus 22% (2/9) in the placebo arm after week 5 (odds ratio, 10.5; 95% confidence interval, 1.1-98.9; P = .044).
Two of the LGI-1 subjects in the IVIG arm were completely seizure free after treatment. Results in both arms, meanwhile, did not correlate with concomitant antiseizure medications among those who were on them.
All eight IVIG patients showed stabilization or improvement in cognitive function, compared with two of five in the placebo arm, as gauged by Repeatable Battery for the Assessment of Neuropsychological Status scores. Patients in the IVIG arm gained a median of 3 points, while patients in the placebo arm lost a median of 1 point (P = .077).
At week 5, six patients with persistent seizures who were in the placebo group were switched to the IVIG regimen after unblinding; four (67%) reported more than a 50% reduction in seizures.
Responses did not correlate with LGI-1/CASPR2-IgG1-4 subclass, and there were no IVIG-associated adverse events. One IVIG patients fell because of a faciobrachial dystonic seizure, a classic sign of LGI-1 disease. Antibodies were not measured in the trial because they “do not correlate with severity of autoimmune epilepsy,” Dr. Dubey said.
The original plan was to enroll 30 subjects, but the investigators terminated the study after 18 because of slow enrollment. With knowledge of autoimmune epilepsy growing at Mayo, it was increasingly difficult to find immunotherapy-naive patients, he said.
All the subjects were between 60 and 70 years old, and the majority in both arms were men, which was not surprising because the conditions skew male, Dr. Dubey said. None of the patients had underlying tumors, which are known triggers of autoimmune epilepsy.
This work was funded by Grifols Shared Services, a maker of IVIG, and Option Care, a provider of home infusion equipment. Dr. Dubey said the company had no active role in the trial, but that the lack of insurance coverage for IVIG in autoimmune epilepsy was one of the drivers of the study. He disclosed research support from Grifols; another investigator is a consultant.
SOURCE: Dubey D et al. AES 2019, Abstract 1.292.
BALTIMORE –
Although the numbers of enrolled subjects was small, it was the first double-blind, placebo-controlled randomized trial in autoimmune epilepsy, the start of a level 1 evidence base. Until now, treatment has been based mostly on case reports and expert opinion. “We’ve clearly shown that immunotherapy works and that treating early makes a difference, much more so than antiseizure medications,” said lead author Divyanshu Dubey, MBBS, from the Mayo Clinic.
The lack of data has meant that “we couldn’t get insurance approval for IVIG, so people have generally leaned towards” high-dose intravenous steroids, which are problematic because LGI-1 antibody epilepsy is a disease of older people, in whom osteoporosis, underlying infections, and other problems complicate steroid use, Dr. Dubey said.
The trial also included three people with contactin-associated-protein-like-2 (CASPR2) antibody epilepsy, but they all wound up in the placebo arm, “so it’s hard to say anything about them,” Dr. Dubey said at the American Epilepsy Society annual meeting. The work was published shortly before the meeting (Ann Neurol. 2019 Nov 28. doi: 10.1002/ana.25655).
CASPR2 and LGI-1 are proteins found in brain cells; attack by antibodies triggers encephalitis and tens to hundreds of seizures per day. The seizures tend to diminish with time, but the cognitive damage caused by the encephalitis does not. “We’ve seen patients end up in nursing homes diagnosed with Alzheimer’s disease” because the conditions weren’t recognized and treated, Dr. Dubey said.
He and his team chose LGI-1 and CASPR2 epilepsy because of the potentially devastating consequences and because they are among the most common autoimmune epilepsies for which antibodies have been identified. There was also a hope that positive results might open up insurance coverage.
The trial randomized eight people to IVIG 0.5 g/kg on day 1; 1 g/kg on day 2; and 0.6 g/kg once at 3 and 5 weeks. Nine others were randomized to volume-matched IV saline placebo on the same schedule. After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated because of slow enrollment.
Although none of the LGI-1 subjects in the placebo group responded, two CASPR2 patients did, yielding an IVIG response rate of 75% versus 22% (2/9) in the placebo arm after week 5 (odds ratio, 10.5; 95% confidence interval, 1.1-98.9; P = .044).
Two of the LGI-1 subjects in the IVIG arm were completely seizure free after treatment. Results in both arms, meanwhile, did not correlate with concomitant antiseizure medications among those who were on them.
All eight IVIG patients showed stabilization or improvement in cognitive function, compared with two of five in the placebo arm, as gauged by Repeatable Battery for the Assessment of Neuropsychological Status scores. Patients in the IVIG arm gained a median of 3 points, while patients in the placebo arm lost a median of 1 point (P = .077).
At week 5, six patients with persistent seizures who were in the placebo group were switched to the IVIG regimen after unblinding; four (67%) reported more than a 50% reduction in seizures.
Responses did not correlate with LGI-1/CASPR2-IgG1-4 subclass, and there were no IVIG-associated adverse events. One IVIG patients fell because of a faciobrachial dystonic seizure, a classic sign of LGI-1 disease. Antibodies were not measured in the trial because they “do not correlate with severity of autoimmune epilepsy,” Dr. Dubey said.
The original plan was to enroll 30 subjects, but the investigators terminated the study after 18 because of slow enrollment. With knowledge of autoimmune epilepsy growing at Mayo, it was increasingly difficult to find immunotherapy-naive patients, he said.
All the subjects were between 60 and 70 years old, and the majority in both arms were men, which was not surprising because the conditions skew male, Dr. Dubey said. None of the patients had underlying tumors, which are known triggers of autoimmune epilepsy.
This work was funded by Grifols Shared Services, a maker of IVIG, and Option Care, a provider of home infusion equipment. Dr. Dubey said the company had no active role in the trial, but that the lack of insurance coverage for IVIG in autoimmune epilepsy was one of the drivers of the study. He disclosed research support from Grifols; another investigator is a consultant.
SOURCE: Dubey D et al. AES 2019, Abstract 1.292.
REPORTING FROM AES 2019
Survival data reported from largest CAR T trial in B-cell lymphoma
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
ORLANDO – Updated results from the TRANSCEND NHL trial include survival data with lisocabtagene maraleucel (liso-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory B-cell lymphomas.
The median progression-free survival (PFS) was 6.8 months, and the median overall survival was 21.1 months. PFS results were best among complete responders and among patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma.
Jeremy S. Abramson, MD, of Massachusetts General Hospital in Boston, presented these results at the annual meeting of the American Society of Hematology.
“TRANSCEND NHL is the largest clinical study to date of CD19-directed CAR T cells in patients with relapsed/refractory aggressive B-cell lymphoma,” Dr. Abramson said.
The phase 1 trial (NCT02631044) includes 269 patients who received liso-cel. They were diagnosed with transformed follicular lymphoma (22%) or other indolent lymphoma (7%), high-grade B-cell lymphoma (13%), primary mediastinal large B-cell lymphoma (6%), grade 3B follicular lymphoma (1%), or diffuse large B-cell lymphoma not otherwise specified (51%).
At baseline, patients had received a median of three prior systemic therapies (range, one to eight). Some patients had received autologous (33%) or allogeneic (3%) transplant. Many patients were chemotherapy refractory (67%) or had never achieved a complete response to prior therapy (44%).
More than half of patients (59%) received bridging therapy during liso-cel manufacturing. All patients received lymphodepletion with fludarabine and cyclophosphamide, followed by liso-cel at 50 x 106 CAR T cells, 100 x 106 CAR T cells, or 150 x 106 CAR T cells.
Response and survival
The median follow-up was 12.0 months. The overall response rate was 73%, and the complete response rate was 53%.
“Remissions were rapid, with a median of 1 month from CAR T-cell infusion, and durable, with a median duration of response that has not been reached and 55% of patients remaining in response at 1 year,” Dr. Abramson said.
The median PFS was 6.8 months overall, not reached for patients who achieved a complete response, 2.8 months for patients with a partial response, and 1.1 months for patients with stable disease or progressive disease.
The median PFS was not reached for patients with primary mediastinal large B-cell lymphoma or transformed follicular lymphoma, 5.0 months for high-grade B-cell lymphoma, 3.0 months for diffuse large B-cell lymphoma not otherwise specified, and 2.9 months in transformed indolent non-Hodgkin lymphoma.
The median overall survival was 21.1 months overall, not reached for patients who achieved a complete response, 9.0 months for patients who had a partial response, and 5.1 months for patients with stable disease or progressive disease.
Safety
Common treatment-emergent adverse events were neutropenia (63%), anemia (48%), fatigue (44%), nausea (33%), thrombocytopenia (31%), headache (30%), decreased appetite (28%), and diarrhea (26%).
Cytokine release syndrome (CRS) occurred in 42% of patients, and neurologic events occurred in 30%. Grade 3-4 CRS occurred in 2% of patients, and grade 3-4 neurologic events occurred in 10%. There were no cases of grade 5 CRS or neurologic events.
The median time to CRS onset was 5 days, and the median time to onset of neurologic events was 9 days. The median time to resolution of CRS and neurologic events was 5 days and 11 days, respectively.
“The low incidence of severe CRS and neurologic events and their late time of onset support using this product in a large range of patients and in the outpatient setting,” Dr. Abramson said.
There were seven grade 5 treatment-related adverse events, including diffuse alveolar damage, pulmonary hemorrhage, multiple organ dysfunction syndrome, cardiomyopathy, fludarabine leukoencephalopathy, septic shock, and progressive multifocal leukoencephalopathy.
This trial is sponsored by Bristol-Myers Squibb. Dr. Abramson reported relationships with Juno Therapeutics and Celgene, now owned by Bristol-Myers Squibb, and a range of other companies.
SOURCE: Abramson JS et al. ASH 2019, Abstract 241.
REPORTING FROM ASH 2019
Developing a career in nutrition support and small-bowel disorders
The role of diet and nutrition is becoming increasingly recognized in the cause, management, and prevention of disease. Despite the clear importance of the role of nutrition in the field of medicine, among health professionals, formal training in nutrition support is lacking. A lack of nutrition training has been recognized in multiple subspecialty fields1 and is highlighted by a shortage of physicians trained to manage disease-related malnutrition.2 Gastroenterologists, in particular, have a special responsibility related to nutrition in disorders of the gastrointestinal tract and are in a unique position to recognize and manage disorders of maldigestion and malabsorption. Unfortunately, surveys of both U.S. and Canadian fellows have demonstrated deficiencies in the training of nutrition support and management of enteral and parenteral nutrition (PN).3,4
Current status of nutrition training
The impact of diet and nutrition on health and disease is universally recognized but unfortunately lagging with respect to formal training at all levels of medical education. A survey of program directors from primary care, surgery, and anesthesia showed only 26% of respondent programs had a formal curriculum in nutrition education.1 Specific to gastroenterology, a majority of trainees and recent graduates perceived that nutrition education was an important aspect of their training; however, only 50% of respondents had training in nutrition support with 36% reporting mandatory training.3
The Gastroenterology Core Curriculum, most recently updated in 2007 – and sponsored by the American Association for the Study of Liver Diseases, American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, and the American Gastroenterological Association – includes six domains of nutrition training within the training track: nutrition assessment, basic nutrition requirements, specific gastrointestinal disorders and other allied diseases, enteral nutrition, PN, and diet therapy. Level 1 training is expected for all gastroenterology fellows. Level 2 is comprised, on average, of an additional 12 months with described objectives, either occurring outside of a standard gastroenterology fellowship or coinciding with a dedicated third year of training. Although training durations for level 1 are not defined, level 2 recommends at least 6 months of experience working with an inpatient nutrition support team (NST) and the management of outpatients in nutrition and weight management clinics.5
Role of a nutrition support team
Training in nutrition is a heterogeneous field, with a wide range that covers understanding metabolism in health and disease, micronutrient and macronutrient requirements, nutrient digestion and absorption, and the best route and provision of nutrition support. Therefore, a critical aspect of education includes access to a dedicated NST. Such teams were common and necessary in the late 1900s with the inception of specialized nutrition therapy. However, with an increase in the use of home infusion therapies, NSTs were dismantled in favor of shifting responsibility to decentralized home infusion companies. A dedicated NST often will include some combination of pharmacists with an interest in the safe compounding of parenteral formulas, nurses with experience in the home management of intravenous therapies and catheters, and dietitians with dedicated interests in intestinal failure, recognition of malnutrition, and provision of calories. Collectively, a highly functioning NST also provides dedicated multidisciplinary training to health professionals of varying backgrounds.
My entry into the field of nutrition support
Entering a fellowship in gastroenterology should be pursued with an open mind. We all have varying experiences in the management of patients with gastrointestinal conditions, both in the inpatient and outpatient arenas through residency training. My early experiences in fellowship at the University of Chicago centered on the management of patients with inflammatory bowel disease (IBD) and with research interests related to the clinical course of IBD. I was also fortunate to be part of a fellowship program offering both level 1 and level 2 training with a longstanding track record of graduating fellows responsible for the running of NSTs at their local institutions. Categorical fellows spend 3 months of training on a rotation with combined inpatient and outpatient responsibilities focusing on the management of patients with intestinal failure, inpatient management of complications from PN support, and an outpatient clinic focused on small-bowel disorders (celiac disease, small-bowel bleeding, and intestinal malabsorption). This experience led me to pursue level 2 training at Northwestern University with a combined focus on small-bowel diseases and enteroscopy.
These collective experiences in fellowship and postfellowship training grounded my ideas on the role of nutrition pervading many gastrointestinal conditions from acute and chronic pancreatitis and IBD to rare conditions such as enteropathy associated with immune deficiencies and autoimmune enteropathy. Now, as a junior faculty member with a focus in nutrition support and small-bowel disorders, my clinical responsibilities include a dedicated half-day in the management of outpatients (parenteral and enteral nutrition), inpatient rounding with our dedicated NST focusing on the initiation of PN, management of home PN complications, and dedicated procedural time focusing on enteral access techniques (percutaneous gastrostomy/jejunostomy tubes) and small-bowel enteroscopy. To my surprise, entry into the field of nutrition support and small-bowel disorders has been filled with excitement and a growing list of collaborations and opportunities. While initial work in the management of PN has been in existence since the 1970s and earlier with respect to the development of safe administration techniques, most of my current work transcends specialties as we develop appropriateness criteria related to PN support in collaboration with a wide range of specialties that include surgery, oncology, and palliative care.
Seeking opportunities for additional training
As the field of gastroenterology grows outward in various directions, mastery of subjects has led to subspecialization in specific areas including interventional gastroenterology, pancreatology, IBD, and motility disorders. The field is primed for broader access to specialty training in nutrition support and small-bowel disorders. Exposure to dedicated training in nutrition and nutrition-related disorders is vital as part of a categorical fellowship, but can also be complemented via visiting observerships, access to formal level 2 training programs, and external programs related to promoting nutrition education.
Since 2001, formal nutrition fellowship programs offering level 2 training have been compiled by the National Board of Physician Nutrition Specialists, although attraction of interested fellows has been lacking.2 The Nestlé Nutrition Institute Clinical Nutrition Fellowship, endorsed by the American Society for Parenteral and Enteral Nutrition and the AGA, is an ongoing program that pairs interested trainees with expert program faculty through onsite clinical rotations lasting a total of 4 weeks.2 Attendance at national and international conferences can supplement a fellows training in nutrition, and an increased focus on nutrition lectures should be a priority of meeting education committees to increase the exposure of trainees to leaders in the field.
Conclusion
A career in nutrition support and small-bowel disorders is incredibly rewarding as it incorporates the basic physiologic processes of digestion and absorption with a wide array of pathologic conditions. Incorporation of the basic principles of intestinal absorption allows for a greater understanding of the role of the low–fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet in the management of irritable bowel syndrome to the varying principles of diets currently under study for the management of IBD. Outside of this spectrum, working with an NST allows for the management of complex cases of malnutrition resulting from disorders ranging from cancer to various postsurgical intestinal alterations. Although observerships and external training programs allow for an introduction into the field, formal level 2 training, combining both work with a NST and small-bowel enteroscopy, allows for exposure to the full range of disorders of the small bowel. As patients continue to seek disease management options rooted in diet, the demand for gastroenterologists with subspecialty training in nutritional disorders will continue to grow and will require further support across training programs to incorporate additional training into categorical fellowships.
References
1. Daley BJ et al. JPEN J Paren Enteral Nutr. 2016;40(1):95-9. doi: 10.1177/0148607115571155.
2. Kiraly LN et al. Nutr Clin Pract. 2014;29(3):332-7. doi: 10.1177/0884533614525212.
3. Hu J et al. Nutr Clin Pract. 2018 Apr;33(2):191-7. doi: 10.1177/0884533617700852.
4. Scolapio JS et al. J Clin Gastroenterol. 2008 Feb;42(2):122-7. doi: 10.1097/MCG.0b013e3181595b6a.
5. American Association for the Study of Liver Diseases et al. The Gastroenterology Core Curriculum, 3rd ed. Gastroenterology. 2007;132(5):2012-8. doi: 10.1053/j.gastro.2007.03.079.
Dr. Micic is assistant professor of medicine, department of internal medicine, section of gastroenterology, hepatology, and nutrition, University of Chicago.
The role of diet and nutrition is becoming increasingly recognized in the cause, management, and prevention of disease. Despite the clear importance of the role of nutrition in the field of medicine, among health professionals, formal training in nutrition support is lacking. A lack of nutrition training has been recognized in multiple subspecialty fields1 and is highlighted by a shortage of physicians trained to manage disease-related malnutrition.2 Gastroenterologists, in particular, have a special responsibility related to nutrition in disorders of the gastrointestinal tract and are in a unique position to recognize and manage disorders of maldigestion and malabsorption. Unfortunately, surveys of both U.S. and Canadian fellows have demonstrated deficiencies in the training of nutrition support and management of enteral and parenteral nutrition (PN).3,4
Current status of nutrition training
The impact of diet and nutrition on health and disease is universally recognized but unfortunately lagging with respect to formal training at all levels of medical education. A survey of program directors from primary care, surgery, and anesthesia showed only 26% of respondent programs had a formal curriculum in nutrition education.1 Specific to gastroenterology, a majority of trainees and recent graduates perceived that nutrition education was an important aspect of their training; however, only 50% of respondents had training in nutrition support with 36% reporting mandatory training.3
The Gastroenterology Core Curriculum, most recently updated in 2007 – and sponsored by the American Association for the Study of Liver Diseases, American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, and the American Gastroenterological Association – includes six domains of nutrition training within the training track: nutrition assessment, basic nutrition requirements, specific gastrointestinal disorders and other allied diseases, enteral nutrition, PN, and diet therapy. Level 1 training is expected for all gastroenterology fellows. Level 2 is comprised, on average, of an additional 12 months with described objectives, either occurring outside of a standard gastroenterology fellowship or coinciding with a dedicated third year of training. Although training durations for level 1 are not defined, level 2 recommends at least 6 months of experience working with an inpatient nutrition support team (NST) and the management of outpatients in nutrition and weight management clinics.5
Role of a nutrition support team
Training in nutrition is a heterogeneous field, with a wide range that covers understanding metabolism in health and disease, micronutrient and macronutrient requirements, nutrient digestion and absorption, and the best route and provision of nutrition support. Therefore, a critical aspect of education includes access to a dedicated NST. Such teams were common and necessary in the late 1900s with the inception of specialized nutrition therapy. However, with an increase in the use of home infusion therapies, NSTs were dismantled in favor of shifting responsibility to decentralized home infusion companies. A dedicated NST often will include some combination of pharmacists with an interest in the safe compounding of parenteral formulas, nurses with experience in the home management of intravenous therapies and catheters, and dietitians with dedicated interests in intestinal failure, recognition of malnutrition, and provision of calories. Collectively, a highly functioning NST also provides dedicated multidisciplinary training to health professionals of varying backgrounds.
My entry into the field of nutrition support
Entering a fellowship in gastroenterology should be pursued with an open mind. We all have varying experiences in the management of patients with gastrointestinal conditions, both in the inpatient and outpatient arenas through residency training. My early experiences in fellowship at the University of Chicago centered on the management of patients with inflammatory bowel disease (IBD) and with research interests related to the clinical course of IBD. I was also fortunate to be part of a fellowship program offering both level 1 and level 2 training with a longstanding track record of graduating fellows responsible for the running of NSTs at their local institutions. Categorical fellows spend 3 months of training on a rotation with combined inpatient and outpatient responsibilities focusing on the management of patients with intestinal failure, inpatient management of complications from PN support, and an outpatient clinic focused on small-bowel disorders (celiac disease, small-bowel bleeding, and intestinal malabsorption). This experience led me to pursue level 2 training at Northwestern University with a combined focus on small-bowel diseases and enteroscopy.
These collective experiences in fellowship and postfellowship training grounded my ideas on the role of nutrition pervading many gastrointestinal conditions from acute and chronic pancreatitis and IBD to rare conditions such as enteropathy associated with immune deficiencies and autoimmune enteropathy. Now, as a junior faculty member with a focus in nutrition support and small-bowel disorders, my clinical responsibilities include a dedicated half-day in the management of outpatients (parenteral and enteral nutrition), inpatient rounding with our dedicated NST focusing on the initiation of PN, management of home PN complications, and dedicated procedural time focusing on enteral access techniques (percutaneous gastrostomy/jejunostomy tubes) and small-bowel enteroscopy. To my surprise, entry into the field of nutrition support and small-bowel disorders has been filled with excitement and a growing list of collaborations and opportunities. While initial work in the management of PN has been in existence since the 1970s and earlier with respect to the development of safe administration techniques, most of my current work transcends specialties as we develop appropriateness criteria related to PN support in collaboration with a wide range of specialties that include surgery, oncology, and palliative care.
Seeking opportunities for additional training
As the field of gastroenterology grows outward in various directions, mastery of subjects has led to subspecialization in specific areas including interventional gastroenterology, pancreatology, IBD, and motility disorders. The field is primed for broader access to specialty training in nutrition support and small-bowel disorders. Exposure to dedicated training in nutrition and nutrition-related disorders is vital as part of a categorical fellowship, but can also be complemented via visiting observerships, access to formal level 2 training programs, and external programs related to promoting nutrition education.
Since 2001, formal nutrition fellowship programs offering level 2 training have been compiled by the National Board of Physician Nutrition Specialists, although attraction of interested fellows has been lacking.2 The Nestlé Nutrition Institute Clinical Nutrition Fellowship, endorsed by the American Society for Parenteral and Enteral Nutrition and the AGA, is an ongoing program that pairs interested trainees with expert program faculty through onsite clinical rotations lasting a total of 4 weeks.2 Attendance at national and international conferences can supplement a fellows training in nutrition, and an increased focus on nutrition lectures should be a priority of meeting education committees to increase the exposure of trainees to leaders in the field.
Conclusion
A career in nutrition support and small-bowel disorders is incredibly rewarding as it incorporates the basic physiologic processes of digestion and absorption with a wide array of pathologic conditions. Incorporation of the basic principles of intestinal absorption allows for a greater understanding of the role of the low–fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet in the management of irritable bowel syndrome to the varying principles of diets currently under study for the management of IBD. Outside of this spectrum, working with an NST allows for the management of complex cases of malnutrition resulting from disorders ranging from cancer to various postsurgical intestinal alterations. Although observerships and external training programs allow for an introduction into the field, formal level 2 training, combining both work with a NST and small-bowel enteroscopy, allows for exposure to the full range of disorders of the small bowel. As patients continue to seek disease management options rooted in diet, the demand for gastroenterologists with subspecialty training in nutritional disorders will continue to grow and will require further support across training programs to incorporate additional training into categorical fellowships.
References
1. Daley BJ et al. JPEN J Paren Enteral Nutr. 2016;40(1):95-9. doi: 10.1177/0148607115571155.
2. Kiraly LN et al. Nutr Clin Pract. 2014;29(3):332-7. doi: 10.1177/0884533614525212.
3. Hu J et al. Nutr Clin Pract. 2018 Apr;33(2):191-7. doi: 10.1177/0884533617700852.
4. Scolapio JS et al. J Clin Gastroenterol. 2008 Feb;42(2):122-7. doi: 10.1097/MCG.0b013e3181595b6a.
5. American Association for the Study of Liver Diseases et al. The Gastroenterology Core Curriculum, 3rd ed. Gastroenterology. 2007;132(5):2012-8. doi: 10.1053/j.gastro.2007.03.079.
Dr. Micic is assistant professor of medicine, department of internal medicine, section of gastroenterology, hepatology, and nutrition, University of Chicago.
The role of diet and nutrition is becoming increasingly recognized in the cause, management, and prevention of disease. Despite the clear importance of the role of nutrition in the field of medicine, among health professionals, formal training in nutrition support is lacking. A lack of nutrition training has been recognized in multiple subspecialty fields1 and is highlighted by a shortage of physicians trained to manage disease-related malnutrition.2 Gastroenterologists, in particular, have a special responsibility related to nutrition in disorders of the gastrointestinal tract and are in a unique position to recognize and manage disorders of maldigestion and malabsorption. Unfortunately, surveys of both U.S. and Canadian fellows have demonstrated deficiencies in the training of nutrition support and management of enteral and parenteral nutrition (PN).3,4
Current status of nutrition training
The impact of diet and nutrition on health and disease is universally recognized but unfortunately lagging with respect to formal training at all levels of medical education. A survey of program directors from primary care, surgery, and anesthesia showed only 26% of respondent programs had a formal curriculum in nutrition education.1 Specific to gastroenterology, a majority of trainees and recent graduates perceived that nutrition education was an important aspect of their training; however, only 50% of respondents had training in nutrition support with 36% reporting mandatory training.3
The Gastroenterology Core Curriculum, most recently updated in 2007 – and sponsored by the American Association for the Study of Liver Diseases, American College of Gastroenterology, the American Society for Gastrointestinal Endoscopy, and the American Gastroenterological Association – includes six domains of nutrition training within the training track: nutrition assessment, basic nutrition requirements, specific gastrointestinal disorders and other allied diseases, enteral nutrition, PN, and diet therapy. Level 1 training is expected for all gastroenterology fellows. Level 2 is comprised, on average, of an additional 12 months with described objectives, either occurring outside of a standard gastroenterology fellowship or coinciding with a dedicated third year of training. Although training durations for level 1 are not defined, level 2 recommends at least 6 months of experience working with an inpatient nutrition support team (NST) and the management of outpatients in nutrition and weight management clinics.5
Role of a nutrition support team
Training in nutrition is a heterogeneous field, with a wide range that covers understanding metabolism in health and disease, micronutrient and macronutrient requirements, nutrient digestion and absorption, and the best route and provision of nutrition support. Therefore, a critical aspect of education includes access to a dedicated NST. Such teams were common and necessary in the late 1900s with the inception of specialized nutrition therapy. However, with an increase in the use of home infusion therapies, NSTs were dismantled in favor of shifting responsibility to decentralized home infusion companies. A dedicated NST often will include some combination of pharmacists with an interest in the safe compounding of parenteral formulas, nurses with experience in the home management of intravenous therapies and catheters, and dietitians with dedicated interests in intestinal failure, recognition of malnutrition, and provision of calories. Collectively, a highly functioning NST also provides dedicated multidisciplinary training to health professionals of varying backgrounds.
My entry into the field of nutrition support
Entering a fellowship in gastroenterology should be pursued with an open mind. We all have varying experiences in the management of patients with gastrointestinal conditions, both in the inpatient and outpatient arenas through residency training. My early experiences in fellowship at the University of Chicago centered on the management of patients with inflammatory bowel disease (IBD) and with research interests related to the clinical course of IBD. I was also fortunate to be part of a fellowship program offering both level 1 and level 2 training with a longstanding track record of graduating fellows responsible for the running of NSTs at their local institutions. Categorical fellows spend 3 months of training on a rotation with combined inpatient and outpatient responsibilities focusing on the management of patients with intestinal failure, inpatient management of complications from PN support, and an outpatient clinic focused on small-bowel disorders (celiac disease, small-bowel bleeding, and intestinal malabsorption). This experience led me to pursue level 2 training at Northwestern University with a combined focus on small-bowel diseases and enteroscopy.
These collective experiences in fellowship and postfellowship training grounded my ideas on the role of nutrition pervading many gastrointestinal conditions from acute and chronic pancreatitis and IBD to rare conditions such as enteropathy associated with immune deficiencies and autoimmune enteropathy. Now, as a junior faculty member with a focus in nutrition support and small-bowel disorders, my clinical responsibilities include a dedicated half-day in the management of outpatients (parenteral and enteral nutrition), inpatient rounding with our dedicated NST focusing on the initiation of PN, management of home PN complications, and dedicated procedural time focusing on enteral access techniques (percutaneous gastrostomy/jejunostomy tubes) and small-bowel enteroscopy. To my surprise, entry into the field of nutrition support and small-bowel disorders has been filled with excitement and a growing list of collaborations and opportunities. While initial work in the management of PN has been in existence since the 1970s and earlier with respect to the development of safe administration techniques, most of my current work transcends specialties as we develop appropriateness criteria related to PN support in collaboration with a wide range of specialties that include surgery, oncology, and palliative care.
Seeking opportunities for additional training
As the field of gastroenterology grows outward in various directions, mastery of subjects has led to subspecialization in specific areas including interventional gastroenterology, pancreatology, IBD, and motility disorders. The field is primed for broader access to specialty training in nutrition support and small-bowel disorders. Exposure to dedicated training in nutrition and nutrition-related disorders is vital as part of a categorical fellowship, but can also be complemented via visiting observerships, access to formal level 2 training programs, and external programs related to promoting nutrition education.
Since 2001, formal nutrition fellowship programs offering level 2 training have been compiled by the National Board of Physician Nutrition Specialists, although attraction of interested fellows has been lacking.2 The Nestlé Nutrition Institute Clinical Nutrition Fellowship, endorsed by the American Society for Parenteral and Enteral Nutrition and the AGA, is an ongoing program that pairs interested trainees with expert program faculty through onsite clinical rotations lasting a total of 4 weeks.2 Attendance at national and international conferences can supplement a fellows training in nutrition, and an increased focus on nutrition lectures should be a priority of meeting education committees to increase the exposure of trainees to leaders in the field.
Conclusion
A career in nutrition support and small-bowel disorders is incredibly rewarding as it incorporates the basic physiologic processes of digestion and absorption with a wide array of pathologic conditions. Incorporation of the basic principles of intestinal absorption allows for a greater understanding of the role of the low–fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet in the management of irritable bowel syndrome to the varying principles of diets currently under study for the management of IBD. Outside of this spectrum, working with an NST allows for the management of complex cases of malnutrition resulting from disorders ranging from cancer to various postsurgical intestinal alterations. Although observerships and external training programs allow for an introduction into the field, formal level 2 training, combining both work with a NST and small-bowel enteroscopy, allows for exposure to the full range of disorders of the small bowel. As patients continue to seek disease management options rooted in diet, the demand for gastroenterologists with subspecialty training in nutritional disorders will continue to grow and will require further support across training programs to incorporate additional training into categorical fellowships.
References
1. Daley BJ et al. JPEN J Paren Enteral Nutr. 2016;40(1):95-9. doi: 10.1177/0148607115571155.
2. Kiraly LN et al. Nutr Clin Pract. 2014;29(3):332-7. doi: 10.1177/0884533614525212.
3. Hu J et al. Nutr Clin Pract. 2018 Apr;33(2):191-7. doi: 10.1177/0884533617700852.
4. Scolapio JS et al. J Clin Gastroenterol. 2008 Feb;42(2):122-7. doi: 10.1097/MCG.0b013e3181595b6a.
5. American Association for the Study of Liver Diseases et al. The Gastroenterology Core Curriculum, 3rd ed. Gastroenterology. 2007;132(5):2012-8. doi: 10.1053/j.gastro.2007.03.079.
Dr. Micic is assistant professor of medicine, department of internal medicine, section of gastroenterology, hepatology, and nutrition, University of Chicago.
Pitfalls in physician-patient communication via patient access support portals
Technology can be used to enhance communication, increase patient safety, and improve overall patient care. For example, many physicians have arranged for remote access to medical records and established a unique system of communication via a patient access support portal. A patient portal is a secure online website that provides patients 24-hour, on-demand access to their health information. Patient portals, while popular and oftentimes quite helpful, are not without drawbacks. Communication by electronic means with your patient can be viewed by some as impersonal and can make patients less tolerant to what they perceive to be a mistake, error, or unwanted outcome. A decrease in face-to-face contact and communication with your patient also gives you less time to resolve any conflict or disagreement. While communication via a patient access support portal has the potential to free up medical staff for direct patient care, such communication also carries liability risk.
Patient access support portal
A physician’s legal responsibility to communicate in a timely and accurate manner does not change, irrespective of the form of communication. However, communication via a patient access portal does have some unique features that must be considered by the practitioner. Practitioners must remember that any communication via the patient portal creates a permanent record, which can and will be used in the event of litigation. For example, when responding to a patient inquiry about a specific complaint, treatment provided, or test result, it will be presumed that the physician had access to the patient’s full medical record and that the full record will be utilized in making a response. Accessing the patient’s chart will leave an audit trail that will provide what is known as metadata, which in the context of electronic medical records, is what allows technicians to verify that the patient record was accessed, and it provides details as to when, and for how long it was accessed. These records are frequently pursued in litigation, so you must understand that parties can often re-create an intricate and accurate timeline of events. While state courts are divided on the issue of whether metadata contained within electronic medical records is discoverable, recent federal court decisions have held that such data is discoverable pursuant to the Federal Rules of Civil Procedure. Thus, once a patient has communicated with you via the portal, you will be responsible for responding in an appropriate and prompt fashion. For these reasons, it is imperative that you create an agreement with your patients as to how the portal will be used and clearly set forth the rules for such use.
Patient portal policies and procedures
In creating patient portal user agreements (See "Sample User Agreement," attached below), it is crucial that an agreement clearly identify the policies and procedures for use. A patient portal user agreement should:
- Set forth the rules and regulations for portal use.
- Include a verification procedure that requires the patients to confirm that they have the legal capacity to consent to the terms of use. This is especially important when treating patients with mental disability, elderly patients with dementia, minors, and any other individuals who may not legally consent.
- Include a verification procedure that requires the patients to confirm that they understand and agree to abide by the user agreement rules.
- Include a detailed list that informs users of the risks and benefits of communicating via the patient portal.
- Stress that communication through the patient portal is for nonemergent matters only.
- Set forth permissible topics for use, such as communicating with the physician or staff, obtaining test results or records, and setting, changing, or canceling appointments.
- Clearly indicate certain topics that should not be discussed via the patient portal, including mental health issues.
- Reiterate that communication via the patient portal is only one option, and that all other standard methods of communication remain available. In doing so, provide office telephone numbers, hotlines, and email addresses for convenience.
- Inform the patients that they should call the office with any questions or concerns regarding use of the patient portal.
- Include a statement that the patient should call 911 or proceed directly to the nearest hospital for any and all urgent or emergent medical matters.
Other considerations
There are, however, equally critical considerations to be made that go beyond the core details of the user agreement. For instance, use of the patient access portal should be limited to only current or active patients, and you should stress to patients the importance of keeping their contact information updated and accurate. This is especially vital in situations in which a patient is unresponsive to communication via the portal, as your staff will need to follow up via other means of communication. It is also imperative to ensure the patient portal is programmed to promptly alert you or your staff following an inquiry from the patient as the patient will likely expect an immediate response.
Notably, communication via the patient portal must still comply with the Health Insurance Portability and Accountability Act (HIPAA). This means that only authorized users are able to access records within the patient portal. To ensure compliance with HIPAA, all users should be instructed in the appropriate practices of maintaining patient privacy. This includes barring the use of shared passwords amongst multiple individuals, requiring that users enable an auto log-off setting, and programming work stations to turn off automatically after brief periods of nonuse. Further, all communications in the patient portal should be encrypted to prevent the patient’s sensitive information from being accessed in the event of an attempted security breach.
Finally, depending upon the practice, there may be instances in which someone other than the patient’s physician would be reading and responding to patient queries. In these situations, the patient should be informed of such potential. This way, if the communication is intended only for the physician, the patient will be afforded the opportunity to call the physician directly rather than communicate via the patient portal.
While the use of patient access portals is becoming far more prevalent, as they offer many practical benefits ranging from increased convenience and efficiency to enhanced patient care, they also carry the potential for increased liability exposure. As such, it is vital that physicians weigh all potential risks and benefits that are inherent in the use of patient access portals prior to making the decision to implement such technology.
Mr. Mills is an equity partner in Cunningham, Meyer & Vedrine, Chicago.
Technology can be used to enhance communication, increase patient safety, and improve overall patient care. For example, many physicians have arranged for remote access to medical records and established a unique system of communication via a patient access support portal. A patient portal is a secure online website that provides patients 24-hour, on-demand access to their health information. Patient portals, while popular and oftentimes quite helpful, are not without drawbacks. Communication by electronic means with your patient can be viewed by some as impersonal and can make patients less tolerant to what they perceive to be a mistake, error, or unwanted outcome. A decrease in face-to-face contact and communication with your patient also gives you less time to resolve any conflict or disagreement. While communication via a patient access support portal has the potential to free up medical staff for direct patient care, such communication also carries liability risk.
Patient access support portal
A physician’s legal responsibility to communicate in a timely and accurate manner does not change, irrespective of the form of communication. However, communication via a patient access portal does have some unique features that must be considered by the practitioner. Practitioners must remember that any communication via the patient portal creates a permanent record, which can and will be used in the event of litigation. For example, when responding to a patient inquiry about a specific complaint, treatment provided, or test result, it will be presumed that the physician had access to the patient’s full medical record and that the full record will be utilized in making a response. Accessing the patient’s chart will leave an audit trail that will provide what is known as metadata, which in the context of electronic medical records, is what allows technicians to verify that the patient record was accessed, and it provides details as to when, and for how long it was accessed. These records are frequently pursued in litigation, so you must understand that parties can often re-create an intricate and accurate timeline of events. While state courts are divided on the issue of whether metadata contained within electronic medical records is discoverable, recent federal court decisions have held that such data is discoverable pursuant to the Federal Rules of Civil Procedure. Thus, once a patient has communicated with you via the portal, you will be responsible for responding in an appropriate and prompt fashion. For these reasons, it is imperative that you create an agreement with your patients as to how the portal will be used and clearly set forth the rules for such use.
Patient portal policies and procedures
In creating patient portal user agreements (See "Sample User Agreement," attached below), it is crucial that an agreement clearly identify the policies and procedures for use. A patient portal user agreement should:
- Set forth the rules and regulations for portal use.
- Include a verification procedure that requires the patients to confirm that they have the legal capacity to consent to the terms of use. This is especially important when treating patients with mental disability, elderly patients with dementia, minors, and any other individuals who may not legally consent.
- Include a verification procedure that requires the patients to confirm that they understand and agree to abide by the user agreement rules.
- Include a detailed list that informs users of the risks and benefits of communicating via the patient portal.
- Stress that communication through the patient portal is for nonemergent matters only.
- Set forth permissible topics for use, such as communicating with the physician or staff, obtaining test results or records, and setting, changing, or canceling appointments.
- Clearly indicate certain topics that should not be discussed via the patient portal, including mental health issues.
- Reiterate that communication via the patient portal is only one option, and that all other standard methods of communication remain available. In doing so, provide office telephone numbers, hotlines, and email addresses for convenience.
- Inform the patients that they should call the office with any questions or concerns regarding use of the patient portal.
- Include a statement that the patient should call 911 or proceed directly to the nearest hospital for any and all urgent or emergent medical matters.
Other considerations
There are, however, equally critical considerations to be made that go beyond the core details of the user agreement. For instance, use of the patient access portal should be limited to only current or active patients, and you should stress to patients the importance of keeping their contact information updated and accurate. This is especially vital in situations in which a patient is unresponsive to communication via the portal, as your staff will need to follow up via other means of communication. It is also imperative to ensure the patient portal is programmed to promptly alert you or your staff following an inquiry from the patient as the patient will likely expect an immediate response.
Notably, communication via the patient portal must still comply with the Health Insurance Portability and Accountability Act (HIPAA). This means that only authorized users are able to access records within the patient portal. To ensure compliance with HIPAA, all users should be instructed in the appropriate practices of maintaining patient privacy. This includes barring the use of shared passwords amongst multiple individuals, requiring that users enable an auto log-off setting, and programming work stations to turn off automatically after brief periods of nonuse. Further, all communications in the patient portal should be encrypted to prevent the patient’s sensitive information from being accessed in the event of an attempted security breach.
Finally, depending upon the practice, there may be instances in which someone other than the patient’s physician would be reading and responding to patient queries. In these situations, the patient should be informed of such potential. This way, if the communication is intended only for the physician, the patient will be afforded the opportunity to call the physician directly rather than communicate via the patient portal.
While the use of patient access portals is becoming far more prevalent, as they offer many practical benefits ranging from increased convenience and efficiency to enhanced patient care, they also carry the potential for increased liability exposure. As such, it is vital that physicians weigh all potential risks and benefits that are inherent in the use of patient access portals prior to making the decision to implement such technology.
Mr. Mills is an equity partner in Cunningham, Meyer & Vedrine, Chicago.
Technology can be used to enhance communication, increase patient safety, and improve overall patient care. For example, many physicians have arranged for remote access to medical records and established a unique system of communication via a patient access support portal. A patient portal is a secure online website that provides patients 24-hour, on-demand access to their health information. Patient portals, while popular and oftentimes quite helpful, are not without drawbacks. Communication by electronic means with your patient can be viewed by some as impersonal and can make patients less tolerant to what they perceive to be a mistake, error, or unwanted outcome. A decrease in face-to-face contact and communication with your patient also gives you less time to resolve any conflict or disagreement. While communication via a patient access support portal has the potential to free up medical staff for direct patient care, such communication also carries liability risk.
Patient access support portal
A physician’s legal responsibility to communicate in a timely and accurate manner does not change, irrespective of the form of communication. However, communication via a patient access portal does have some unique features that must be considered by the practitioner. Practitioners must remember that any communication via the patient portal creates a permanent record, which can and will be used in the event of litigation. For example, when responding to a patient inquiry about a specific complaint, treatment provided, or test result, it will be presumed that the physician had access to the patient’s full medical record and that the full record will be utilized in making a response. Accessing the patient’s chart will leave an audit trail that will provide what is known as metadata, which in the context of electronic medical records, is what allows technicians to verify that the patient record was accessed, and it provides details as to when, and for how long it was accessed. These records are frequently pursued in litigation, so you must understand that parties can often re-create an intricate and accurate timeline of events. While state courts are divided on the issue of whether metadata contained within electronic medical records is discoverable, recent federal court decisions have held that such data is discoverable pursuant to the Federal Rules of Civil Procedure. Thus, once a patient has communicated with you via the portal, you will be responsible for responding in an appropriate and prompt fashion. For these reasons, it is imperative that you create an agreement with your patients as to how the portal will be used and clearly set forth the rules for such use.
Patient portal policies and procedures
In creating patient portal user agreements (See "Sample User Agreement," attached below), it is crucial that an agreement clearly identify the policies and procedures for use. A patient portal user agreement should:
- Set forth the rules and regulations for portal use.
- Include a verification procedure that requires the patients to confirm that they have the legal capacity to consent to the terms of use. This is especially important when treating patients with mental disability, elderly patients with dementia, minors, and any other individuals who may not legally consent.
- Include a verification procedure that requires the patients to confirm that they understand and agree to abide by the user agreement rules.
- Include a detailed list that informs users of the risks and benefits of communicating via the patient portal.
- Stress that communication through the patient portal is for nonemergent matters only.
- Set forth permissible topics for use, such as communicating with the physician or staff, obtaining test results or records, and setting, changing, or canceling appointments.
- Clearly indicate certain topics that should not be discussed via the patient portal, including mental health issues.
- Reiterate that communication via the patient portal is only one option, and that all other standard methods of communication remain available. In doing so, provide office telephone numbers, hotlines, and email addresses for convenience.
- Inform the patients that they should call the office with any questions or concerns regarding use of the patient portal.
- Include a statement that the patient should call 911 or proceed directly to the nearest hospital for any and all urgent or emergent medical matters.
Other considerations
There are, however, equally critical considerations to be made that go beyond the core details of the user agreement. For instance, use of the patient access portal should be limited to only current or active patients, and you should stress to patients the importance of keeping their contact information updated and accurate. This is especially vital in situations in which a patient is unresponsive to communication via the portal, as your staff will need to follow up via other means of communication. It is also imperative to ensure the patient portal is programmed to promptly alert you or your staff following an inquiry from the patient as the patient will likely expect an immediate response.
Notably, communication via the patient portal must still comply with the Health Insurance Portability and Accountability Act (HIPAA). This means that only authorized users are able to access records within the patient portal. To ensure compliance with HIPAA, all users should be instructed in the appropriate practices of maintaining patient privacy. This includes barring the use of shared passwords amongst multiple individuals, requiring that users enable an auto log-off setting, and programming work stations to turn off automatically after brief periods of nonuse. Further, all communications in the patient portal should be encrypted to prevent the patient’s sensitive information from being accessed in the event of an attempted security breach.
Finally, depending upon the practice, there may be instances in which someone other than the patient’s physician would be reading and responding to patient queries. In these situations, the patient should be informed of such potential. This way, if the communication is intended only for the physician, the patient will be afforded the opportunity to call the physician directly rather than communicate via the patient portal.
While the use of patient access portals is becoming far more prevalent, as they offer many practical benefits ranging from increased convenience and efficiency to enhanced patient care, they also carry the potential for increased liability exposure. As such, it is vital that physicians weigh all potential risks and benefits that are inherent in the use of patient access portals prior to making the decision to implement such technology.
Mr. Mills is an equity partner in Cunningham, Meyer & Vedrine, Chicago.
Vitamin D alone does not reduce fracture risk
Vitamin D supplementation alone does not appear to reduce the risk of fracture, but a combination of vitamin D and calcium may, according to a systematic review and meta-analysis published in JAMA Network Open.
Pang Yao, PhD, from the Nuffield Department of Population Health at the University of Oxford (England) and coauthors wrote that, while randomized, controlled trials (RCTs) of vitamin D supplements – either alone or in combination with calcium supplementation – have found conflicting results, most only had limited power to detect differences in the risk of fracture.
Dr. Yao and associates performed a meta-analysis of 11 observational studies with 39,141 participants, 11 RCTs of vitamin D supplementation alone in 34,243 participants, and 6 RCTs of calcium plus vitamin D involving 49,282 participants.
The analysis of the observational studies revealed that each 10.0-ng/mL increase in blood 25-hydroxyvitamin D concentrations was associated with a 7% lower risk of any fracture. However the authors noted significant heterogeneity between individual studies.
The meta-analysis of the 11 trials of vitamin D alone found that supplementation was not associated with significant change in the risk for any fracture or for hip fracture. Even subgroup analyses looking at age, residential status, location, study design, daily supplementation, or duration of supplementation failed to find any effect. However, there was a median difference in blood 25-hydroxyvitamin D concentrations of 8.4 ng/mL with vitamin D supplementation.
In the meta-analysis of the six vitamin D plus calcium trials, there was a significant 6% reduction in the rate of any fracture and a 16% reduction in hip fracture rate with supplementation. Overall, there was a 1% reduction in the risk of any fracture for each 0.4-ng/mL difference in blood 25-hydroxyvitamin D concentration and 2% reduction in the risk of hip fracture.
However, the authors judged five of those six vitamin D plus calcium trials to be at high risk of bias, with two having open-label designs, although there was little heterogeneity among the studies. All the trials used either 800 or 400 IU/day of vitamin D and 1,200 or 800 mg/day of calcium, and the mean duration of treatment was 5.9 years.
Participants aged 80 years or older living in institutions showed greater reductions in the risk of any fracture with calcium plus vitamin D supplementation, compared with those younger than 80 years who were living in the community.
“In this systematic review and meta-analysis, the available evidence from completed RCTs provided no support for the effects of vitamin D alone on prevention of fracture, but most of these RCTs were constrained by methodological problems,” they wrote. “Meta-analyses of ongoing RCTs assessing the effects of higher daily doses of vitamin D on fracture risk are needed before making recommendations on the use of vitamin D for prevention of fracture.”
One author was supported by a Sino-British Fellowship Trust scholarship, and another received grants from the U.K. Medical Research Council. No conflicts of interest were declared.
SOURCE: Yao P et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.17789.
Vitamin D supplementation alone does not appear to reduce the risk of fracture, but a combination of vitamin D and calcium may, according to a systematic review and meta-analysis published in JAMA Network Open.
Pang Yao, PhD, from the Nuffield Department of Population Health at the University of Oxford (England) and coauthors wrote that, while randomized, controlled trials (RCTs) of vitamin D supplements – either alone or in combination with calcium supplementation – have found conflicting results, most only had limited power to detect differences in the risk of fracture.
Dr. Yao and associates performed a meta-analysis of 11 observational studies with 39,141 participants, 11 RCTs of vitamin D supplementation alone in 34,243 participants, and 6 RCTs of calcium plus vitamin D involving 49,282 participants.
The analysis of the observational studies revealed that each 10.0-ng/mL increase in blood 25-hydroxyvitamin D concentrations was associated with a 7% lower risk of any fracture. However the authors noted significant heterogeneity between individual studies.
The meta-analysis of the 11 trials of vitamin D alone found that supplementation was not associated with significant change in the risk for any fracture or for hip fracture. Even subgroup analyses looking at age, residential status, location, study design, daily supplementation, or duration of supplementation failed to find any effect. However, there was a median difference in blood 25-hydroxyvitamin D concentrations of 8.4 ng/mL with vitamin D supplementation.
In the meta-analysis of the six vitamin D plus calcium trials, there was a significant 6% reduction in the rate of any fracture and a 16% reduction in hip fracture rate with supplementation. Overall, there was a 1% reduction in the risk of any fracture for each 0.4-ng/mL difference in blood 25-hydroxyvitamin D concentration and 2% reduction in the risk of hip fracture.
However, the authors judged five of those six vitamin D plus calcium trials to be at high risk of bias, with two having open-label designs, although there was little heterogeneity among the studies. All the trials used either 800 or 400 IU/day of vitamin D and 1,200 or 800 mg/day of calcium, and the mean duration of treatment was 5.9 years.
Participants aged 80 years or older living in institutions showed greater reductions in the risk of any fracture with calcium plus vitamin D supplementation, compared with those younger than 80 years who were living in the community.
“In this systematic review and meta-analysis, the available evidence from completed RCTs provided no support for the effects of vitamin D alone on prevention of fracture, but most of these RCTs were constrained by methodological problems,” they wrote. “Meta-analyses of ongoing RCTs assessing the effects of higher daily doses of vitamin D on fracture risk are needed before making recommendations on the use of vitamin D for prevention of fracture.”
One author was supported by a Sino-British Fellowship Trust scholarship, and another received grants from the U.K. Medical Research Council. No conflicts of interest were declared.
SOURCE: Yao P et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.17789.
Vitamin D supplementation alone does not appear to reduce the risk of fracture, but a combination of vitamin D and calcium may, according to a systematic review and meta-analysis published in JAMA Network Open.
Pang Yao, PhD, from the Nuffield Department of Population Health at the University of Oxford (England) and coauthors wrote that, while randomized, controlled trials (RCTs) of vitamin D supplements – either alone or in combination with calcium supplementation – have found conflicting results, most only had limited power to detect differences in the risk of fracture.
Dr. Yao and associates performed a meta-analysis of 11 observational studies with 39,141 participants, 11 RCTs of vitamin D supplementation alone in 34,243 participants, and 6 RCTs of calcium plus vitamin D involving 49,282 participants.
The analysis of the observational studies revealed that each 10.0-ng/mL increase in blood 25-hydroxyvitamin D concentrations was associated with a 7% lower risk of any fracture. However the authors noted significant heterogeneity between individual studies.
The meta-analysis of the 11 trials of vitamin D alone found that supplementation was not associated with significant change in the risk for any fracture or for hip fracture. Even subgroup analyses looking at age, residential status, location, study design, daily supplementation, or duration of supplementation failed to find any effect. However, there was a median difference in blood 25-hydroxyvitamin D concentrations of 8.4 ng/mL with vitamin D supplementation.
In the meta-analysis of the six vitamin D plus calcium trials, there was a significant 6% reduction in the rate of any fracture and a 16% reduction in hip fracture rate with supplementation. Overall, there was a 1% reduction in the risk of any fracture for each 0.4-ng/mL difference in blood 25-hydroxyvitamin D concentration and 2% reduction in the risk of hip fracture.
However, the authors judged five of those six vitamin D plus calcium trials to be at high risk of bias, with two having open-label designs, although there was little heterogeneity among the studies. All the trials used either 800 or 400 IU/day of vitamin D and 1,200 or 800 mg/day of calcium, and the mean duration of treatment was 5.9 years.
Participants aged 80 years or older living in institutions showed greater reductions in the risk of any fracture with calcium plus vitamin D supplementation, compared with those younger than 80 years who were living in the community.
“In this systematic review and meta-analysis, the available evidence from completed RCTs provided no support for the effects of vitamin D alone on prevention of fracture, but most of these RCTs were constrained by methodological problems,” they wrote. “Meta-analyses of ongoing RCTs assessing the effects of higher daily doses of vitamin D on fracture risk are needed before making recommendations on the use of vitamin D for prevention of fracture.”
One author was supported by a Sino-British Fellowship Trust scholarship, and another received grants from the U.K. Medical Research Council. No conflicts of interest were declared.
SOURCE: Yao P et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.17789.
FROM JAMA NETWORK OPEN
Dose escalation of biosimilar infliximab for RA patients deemed cost effective, to a point
A new study has found that although dose escalation is common in RA patients being treated with infliximab, the low price of infliximab biosimilars that are currently commercially available in the United States often outweighs switching to a similarly administered tumor necrosis factor inhibitor with no biosimilar, such as intravenous golimumab (Simponi).
“Given the 21% lower average sales price [ASP] of biosimilar infliximab-dyyb [Inflectra], as compared to the ASP of bio-originator infliximab, in Q3 2019, even infliximab dose[d] at 8 mg/kg [every] 6 weeks should be approximately neutral or cost saving, compared to golimumab IV,” wrote Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and coauthors. The study was published in Arthritis Research & Therapy.
To determine if and when dose escalation of an infliximab biosimilar might offset the cost savings of its use, the researchers launched a cohort study of Medicare enrollees with RA who began treatment in 2013 (when intravenous golimumab first went on the market) through the end of 2016 (biosimilar infliximab-dyyb was first marketed in the United States in November 2016). They analyzed dose escalations and reimbursement amounts through 78 weeks for 5,174 patients who started infliximab and 2,843 patients who started golimumab. The golimumab patients were slightly older (70 years vs. 68.6 years) and more likely to receive monotherapy.
After 18 months, 5% of golimumab patients increased their dose, compared with 49% of infliximab patients (P less than .0001). Of patients who had no gap in infliximab treatment for greater than 10 weeks (n = 1,380), 72% had their dose escalated. Characteristics associated with dose escalation included being younger, being male, and not having chronic pulmonary disease. Physicians who owned their own infusion centers were 25% more likely to escalate doses of infliximab (adjusted odds ratio, 1.25; 95% confidence interval, 1.09-1.44).
Mean costs paid by Medicare for the first 18 months of treatment were significantly higher for golimumab ($28,146; 95% CI, $27,497-$28,810), compared with infliximab ($21,216; 95% CI, $20,737-$21,706). An analysis of patients who persisted on therapy for all 18 months with no treatment gap greater than 10 weeks revealed an even greater disparity in cost: $43,940 for golimumab (95% CI, $42,849-$45,058) versus $34,671 for infliximab (95% CI, $33,891-$35,470).
According to a sensitivity analysis, 34% of infliximab-treated patients increased their dose to 5 mg/kg, 5% increased their dose to 8 mg/kg, and 4% increased their dose to 10 mg/kg. In a modeling scenario that considered cost, dose, and frequency, infliximab at 8 mg/kg dosed every 6 weeks was cheaper than golimumab with a biosimilar discount of greater than 25%. At 10 mg/kg dosed every 6 weeks, infliximab was cheaper than golimumab with a biosimilar discount of 30% or more.
That said, given comparable clinical outcomes with other RA biologics plus the increased indirect costs and greater risk of serious infections associated with infliximab dose escalation, the researchers noted that “escalation beyond 5 mg/kg is probably not a prudent course of treatment for most RA patients, compared to switching to alternative treatment options.”
Though they emphasized their study’s strengths – including the impressive sample size of older Medicare patients – the authors also acknowledged its limitations, such as a lack of information on the clinical reasons for treatment discontinuation and dose escalation. They also were not able to examine whether safety or tolerability played a role in patients’ treatment decisions.
Two of the four authors reported receiving research grants and consulting fees from various medical and pharmaceutical companies, and one other author reported owning stock in Amgen.
SOURCE: Curtis JR et al. Arthritis Res Ther. 2019 Dec 12. doi: 10.1186/s13075-019-2022-8.
A new study has found that although dose escalation is common in RA patients being treated with infliximab, the low price of infliximab biosimilars that are currently commercially available in the United States often outweighs switching to a similarly administered tumor necrosis factor inhibitor with no biosimilar, such as intravenous golimumab (Simponi).
“Given the 21% lower average sales price [ASP] of biosimilar infliximab-dyyb [Inflectra], as compared to the ASP of bio-originator infliximab, in Q3 2019, even infliximab dose[d] at 8 mg/kg [every] 6 weeks should be approximately neutral or cost saving, compared to golimumab IV,” wrote Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and coauthors. The study was published in Arthritis Research & Therapy.
To determine if and when dose escalation of an infliximab biosimilar might offset the cost savings of its use, the researchers launched a cohort study of Medicare enrollees with RA who began treatment in 2013 (when intravenous golimumab first went on the market) through the end of 2016 (biosimilar infliximab-dyyb was first marketed in the United States in November 2016). They analyzed dose escalations and reimbursement amounts through 78 weeks for 5,174 patients who started infliximab and 2,843 patients who started golimumab. The golimumab patients were slightly older (70 years vs. 68.6 years) and more likely to receive monotherapy.
After 18 months, 5% of golimumab patients increased their dose, compared with 49% of infliximab patients (P less than .0001). Of patients who had no gap in infliximab treatment for greater than 10 weeks (n = 1,380), 72% had their dose escalated. Characteristics associated with dose escalation included being younger, being male, and not having chronic pulmonary disease. Physicians who owned their own infusion centers were 25% more likely to escalate doses of infliximab (adjusted odds ratio, 1.25; 95% confidence interval, 1.09-1.44).
Mean costs paid by Medicare for the first 18 months of treatment were significantly higher for golimumab ($28,146; 95% CI, $27,497-$28,810), compared with infliximab ($21,216; 95% CI, $20,737-$21,706). An analysis of patients who persisted on therapy for all 18 months with no treatment gap greater than 10 weeks revealed an even greater disparity in cost: $43,940 for golimumab (95% CI, $42,849-$45,058) versus $34,671 for infliximab (95% CI, $33,891-$35,470).
According to a sensitivity analysis, 34% of infliximab-treated patients increased their dose to 5 mg/kg, 5% increased their dose to 8 mg/kg, and 4% increased their dose to 10 mg/kg. In a modeling scenario that considered cost, dose, and frequency, infliximab at 8 mg/kg dosed every 6 weeks was cheaper than golimumab with a biosimilar discount of greater than 25%. At 10 mg/kg dosed every 6 weeks, infliximab was cheaper than golimumab with a biosimilar discount of 30% or more.
That said, given comparable clinical outcomes with other RA biologics plus the increased indirect costs and greater risk of serious infections associated with infliximab dose escalation, the researchers noted that “escalation beyond 5 mg/kg is probably not a prudent course of treatment for most RA patients, compared to switching to alternative treatment options.”
Though they emphasized their study’s strengths – including the impressive sample size of older Medicare patients – the authors also acknowledged its limitations, such as a lack of information on the clinical reasons for treatment discontinuation and dose escalation. They also were not able to examine whether safety or tolerability played a role in patients’ treatment decisions.
Two of the four authors reported receiving research grants and consulting fees from various medical and pharmaceutical companies, and one other author reported owning stock in Amgen.
SOURCE: Curtis JR et al. Arthritis Res Ther. 2019 Dec 12. doi: 10.1186/s13075-019-2022-8.
A new study has found that although dose escalation is common in RA patients being treated with infliximab, the low price of infliximab biosimilars that are currently commercially available in the United States often outweighs switching to a similarly administered tumor necrosis factor inhibitor with no biosimilar, such as intravenous golimumab (Simponi).
“Given the 21% lower average sales price [ASP] of biosimilar infliximab-dyyb [Inflectra], as compared to the ASP of bio-originator infliximab, in Q3 2019, even infliximab dose[d] at 8 mg/kg [every] 6 weeks should be approximately neutral or cost saving, compared to golimumab IV,” wrote Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and coauthors. The study was published in Arthritis Research & Therapy.
To determine if and when dose escalation of an infliximab biosimilar might offset the cost savings of its use, the researchers launched a cohort study of Medicare enrollees with RA who began treatment in 2013 (when intravenous golimumab first went on the market) through the end of 2016 (biosimilar infliximab-dyyb was first marketed in the United States in November 2016). They analyzed dose escalations and reimbursement amounts through 78 weeks for 5,174 patients who started infliximab and 2,843 patients who started golimumab. The golimumab patients were slightly older (70 years vs. 68.6 years) and more likely to receive monotherapy.
After 18 months, 5% of golimumab patients increased their dose, compared with 49% of infliximab patients (P less than .0001). Of patients who had no gap in infliximab treatment for greater than 10 weeks (n = 1,380), 72% had their dose escalated. Characteristics associated with dose escalation included being younger, being male, and not having chronic pulmonary disease. Physicians who owned their own infusion centers were 25% more likely to escalate doses of infliximab (adjusted odds ratio, 1.25; 95% confidence interval, 1.09-1.44).
Mean costs paid by Medicare for the first 18 months of treatment were significantly higher for golimumab ($28,146; 95% CI, $27,497-$28,810), compared with infliximab ($21,216; 95% CI, $20,737-$21,706). An analysis of patients who persisted on therapy for all 18 months with no treatment gap greater than 10 weeks revealed an even greater disparity in cost: $43,940 for golimumab (95% CI, $42,849-$45,058) versus $34,671 for infliximab (95% CI, $33,891-$35,470).
According to a sensitivity analysis, 34% of infliximab-treated patients increased their dose to 5 mg/kg, 5% increased their dose to 8 mg/kg, and 4% increased their dose to 10 mg/kg. In a modeling scenario that considered cost, dose, and frequency, infliximab at 8 mg/kg dosed every 6 weeks was cheaper than golimumab with a biosimilar discount of greater than 25%. At 10 mg/kg dosed every 6 weeks, infliximab was cheaper than golimumab with a biosimilar discount of 30% or more.
That said, given comparable clinical outcomes with other RA biologics plus the increased indirect costs and greater risk of serious infections associated with infliximab dose escalation, the researchers noted that “escalation beyond 5 mg/kg is probably not a prudent course of treatment for most RA patients, compared to switching to alternative treatment options.”
Though they emphasized their study’s strengths – including the impressive sample size of older Medicare patients – the authors also acknowledged its limitations, such as a lack of information on the clinical reasons for treatment discontinuation and dose escalation. They also were not able to examine whether safety or tolerability played a role in patients’ treatment decisions.
Two of the four authors reported receiving research grants and consulting fees from various medical and pharmaceutical companies, and one other author reported owning stock in Amgen.
SOURCE: Curtis JR et al. Arthritis Res Ther. 2019 Dec 12. doi: 10.1186/s13075-019-2022-8.
FROM ARTHRITIS RESEARCH & THERAPY
Sensitivity of ctDNA equivalent to that of tumor tissue sequencing
SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.
When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.
In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.
“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.
The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).
Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.
Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.
Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.
For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.
Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).
“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.
Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.
Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.
A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.
Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.
Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.
“You indicated there was overall concordance between ddPCR and the targeted capture assay,” Dr. Arteaga said. “That suggests that you did select the better hotspots; however, you could be missing some genomic space captured by the targeted capture assay that may change over time as a function of tumor evolution, drug resistance, or whatever,” Dr. Arteaga said. “So have you assessed how stable that component is as a function of time and treatment, or do you plan to do that?”
Dr. Kingston said that although these data are not yet available, plans are underway to perform ctDNA during the treatment process, so that concordance between the two techniques may be evaluated over time.
The investigators disclosed ties with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.
SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.
When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.
In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.
“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.
The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).
Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.
Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.
Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.
For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.
Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).
“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.
Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.
Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.
A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.
Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.
Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.
“You indicated there was overall concordance between ddPCR and the targeted capture assay,” Dr. Arteaga said. “That suggests that you did select the better hotspots; however, you could be missing some genomic space captured by the targeted capture assay that may change over time as a function of tumor evolution, drug resistance, or whatever,” Dr. Arteaga said. “So have you assessed how stable that component is as a function of time and treatment, or do you plan to do that?”
Dr. Kingston said that although these data are not yet available, plans are underway to perform ctDNA during the treatment process, so that concordance between the two techniques may be evaluated over time.
The investigators disclosed ties with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.
SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.
When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.
In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.
“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.
The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).
Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.
Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.
Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.
For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.
Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).
“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.
Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.
Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.
A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.
Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.
Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.
“You indicated there was overall concordance between ddPCR and the targeted capture assay,” Dr. Arteaga said. “That suggests that you did select the better hotspots; however, you could be missing some genomic space captured by the targeted capture assay that may change over time as a function of tumor evolution, drug resistance, or whatever,” Dr. Arteaga said. “So have you assessed how stable that component is as a function of time and treatment, or do you plan to do that?”
Dr. Kingston said that although these data are not yet available, plans are underway to perform ctDNA during the treatment process, so that concordance between the two techniques may be evaluated over time.
The investigators disclosed ties with Puma Biotechnology, AstraZeneca, Guardant Health, and Bio-Rad.
SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.
REPORTING FROM SABCS 2019
A novel communication framework for inpatient pain management
Introducing the VIEW Framework
Case
A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.
Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
Background
The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.1 In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.
However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.2
SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
The VIEW Framework
VISIT the patient’s chart and your own mental state.
First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.
Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.
While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.
Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.3
Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.2 Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.4,5
INTERVIEW the patient.
Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.
Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
EMPATHIZE with the patient.
Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.6 Use open-ended questions to create space and trust for patients to share their feelings.
Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.6 Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.9
WRAP UP.
Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.
While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
Applying the VIEW framework to the case
Visit
Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.
While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.
She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.
Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
Interview
The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.
When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
Empathize
As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.
She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
Wrap Up
The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.
She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.
She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.
Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.
When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.
During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.
Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.
Key points
- Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
- Review notes and prescription data to better understand past and current pain regimen.
- Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
- Interview patients using a calm tone and nonjudgmental, reassuring words.
- Empathize with patients and validate any frustrations and experience of pain.
- Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.
References
1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.
2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.
3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.
4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.
5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.
6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.
7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.
8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.
9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.
Introducing the VIEW Framework
Introducing the VIEW Framework
Case
A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.
Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
Background
The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.1 In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.
However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.2
SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
The VIEW Framework
VISIT the patient’s chart and your own mental state.
First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.
Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.
While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.
Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.3
Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.2 Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.4,5
INTERVIEW the patient.
Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.
Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
EMPATHIZE with the patient.
Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.6 Use open-ended questions to create space and trust for patients to share their feelings.
Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.6 Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.9
WRAP UP.
Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.
While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
Applying the VIEW framework to the case
Visit
Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.
While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.
She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.
Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
Interview
The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.
When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
Empathize
As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.
She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
Wrap Up
The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.
She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.
She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.
Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.
When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.
During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.
Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.
Key points
- Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
- Review notes and prescription data to better understand past and current pain regimen.
- Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
- Interview patients using a calm tone and nonjudgmental, reassuring words.
- Empathize with patients and validate any frustrations and experience of pain.
- Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.
References
1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.
2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.
3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.
4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.
5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.
6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.
7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.
8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.
9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.
Case
A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.
Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
Background
The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.1 In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.
However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.2
SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
The VIEW Framework
VISIT the patient’s chart and your own mental state.
First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.
Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.
While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.
Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.3
Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.2 Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.4,5
INTERVIEW the patient.
Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.
Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
EMPATHIZE with the patient.
Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.6 Use open-ended questions to create space and trust for patients to share their feelings.
Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.6 Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.9
WRAP UP.
Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.
While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
Applying the VIEW framework to the case
Visit
Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.
While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.
She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.
Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
Interview
The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.
When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
Empathize
As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.
She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
Wrap Up
The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.
She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.
She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.
Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.
When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.
During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.
Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.
Key points
- Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
- Review notes and prescription data to better understand past and current pain regimen.
- Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
- Interview patients using a calm tone and nonjudgmental, reassuring words.
- Empathize with patients and validate any frustrations and experience of pain.
- Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.
References
1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.
2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.
3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.
4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.
5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.
6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.
7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.
8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.
9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.