ORLANDO – Pediatricians who learn about their patients’ lived experience have the potential to encourage patients and help them overcome biases, assumptions, and barriers of opioid use disorder, Tamela Milan said at the American Academy of Pediatrics annual meeting.

After her five children were taken into state welfare custody and she began a sixth pregnancy while struggling with opioid use disorder and as a survivor of domestic violence, Ms. Milan’s pediatrician was the one to encourage her to take steps to improve her life. She went on to regain custody of her children and complete college, and has given back by working in community health programs for over 20 years.

In a video interview, Ms. Milan said she would not have been able to overcome these barriers had it not been for the support of her pediatrician, who saw her as a person instead of a mother with opioid use disorder.

“I’ve been on both sides of the fence,” Ms. Milan said. “As someone who’s had to receive treatment and to provide it, it’s really important that we start looking at people for who they are and where they are.”

Tamela Milan has no relevant conflicts of interest.

ORLANDO – Pediatricians who learn about their patients’ lived experience have the potential to encourage patients and help them overcome biases, assumptions, and barriers of opioid use disorder, Tamela Milan said at the American Academy of Pediatrics annual meeting.

After her five children were taken into state welfare custody and she began a sixth pregnancy while struggling with opioid use disorder and as a survivor of domestic violence, Ms. Milan’s pediatrician was the one to encourage her to take steps to improve her life. She went on to regain custody of her children and complete college, and has given back by working in community health programs for over 20 years.

In a video interview, Ms. Milan said she would not have been able to overcome these barriers had it not been for the support of her pediatrician, who saw her as a person instead of a mother with opioid use disorder.

“I’ve been on both sides of the fence,” Ms. Milan said. “As someone who’s had to receive treatment and to provide it, it’s really important that we start looking at people for who they are and where they are.”

Tamela Milan has no relevant conflicts of interest.

ORLANDO – Pediatricians who learn about their patients’ lived experience have the potential to encourage patients and help them overcome biases, assumptions, and barriers of opioid use disorder, Tamela Milan said at the American Academy of Pediatrics annual meeting.

After her five children were taken into state welfare custody and she began a sixth pregnancy while struggling with opioid use disorder and as a survivor of domestic violence, Ms. Milan’s pediatrician was the one to encourage her to take steps to improve her life. She went on to regain custody of her children and complete college, and has given back by working in community health programs for over 20 years.

In a video interview, Ms. Milan said she would not have been able to overcome these barriers had it not been for the support of her pediatrician, who saw her as a person instead of a mother with opioid use disorder.

“I’ve been on both sides of the fence,” Ms. Milan said. “As someone who’s had to receive treatment and to provide it, it’s really important that we start looking at people for who they are and where they are.”

Tamela Milan has no relevant conflicts of interest.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

SAN DIEGO – A smartphone app that included artificial intelligence elements was associated with improved pain outcomes and reduced hospital admissions in patients with advanced cancers.

Pain severity significantly decreased among patients randomized to use the app versus control patients who received only palliative care, researchers reported at the Palliative and Supportive Care in Oncology Symposium.

The risk of pain-related hospital admissions was significantly lower for those who used the pain tracking app, called ePAL, though anxiety scores were higher in the app users, the investigators said, and no difference between arms was noted in quality of life or global symptom scores.

The ePAL app prompts patients three times per week to track their pain levels and, depending on the severity of pain, will use an algorithm to guide patients through their symptoms, or, in patients with persistent or worsening pain, connect them directly with the palliative care service for additional assessment.

The app also includes pain management tips, among other educational content, provides the ability to request pain prescription refills, and creates a summary of the patient’s pain condition for the provider, said Mihir M. Kamdar, MD, associate director of palliative care at Massachusetts General Hospital in Boston.

“The provider can actually start the visit with that information, instead of having to spend several minutes trying to recap what might or might not have happened since the last clinic visit,” Dr. Kamdar said.

The study included 112 English-speaking adult patients with stage IV solid cancers and moderate to severe pain who were being followed in a palliative care clinic. They were randomly assigned to receive the ePAL app plus standard of care or standard of care alone; 39 patients in the app group and 40 in the control arm completed the 8-week evaluation.

Pain severity, the primary study endpoint, decreased over time in the intervention group, from a composite Brief Pain Inventory score of 3.74 at enrollment to 2.99 at 8 weeks, while in the control group, the scores were 4.02 at enrollment and 4.05 at 8 weeks (P = .017 for intervention versus control), Dr. Kamdar reported.

Risk of pain-related hospital admissions was significantly lower in the intervention group, according to Dr. Kamdar. The per-patient risk of an inpatient admission was 0.071 and 0.232 for the intervention and controls groups, respectively, with a risk ratio of 0.31 (95% CI, 0.11-0.89; P = .018).

Anxiety was increased in the app users, as measured by the Generalized Anxiety Disorder 7-item scale, with a significant difference between the app and control groups at 8 weeks (P = .015). However, the change was in a range considered mild and was not seen in patients who used the app more than two times per week.

Negative attitudes toward cancer pain treatment decreased significantly in the app group, as shown by a lower score on the Barriers Questionnaire II at 8 weeks (P = .042), Dr. Kamdar reported.

The app and study were supported by the McKesson Foundation’s Mobilizing for Health Initiative. Dr. Kamdar reported stock/ownership and consulting/advisory role disclosures related to Amorsa Therapeutics.

SOURCE: Kamdar MM et al. PallOnc 2018, Abstract 76.

CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).

The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.

Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
 

The ACR CRISS

Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).

Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).

A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.

Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.

This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.

Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.

New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
 

The focuSSced study of tocilizumab

For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.

However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.

The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.

Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.

Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.

“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
 

The ASSET trial of abatacept

Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.

Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).

And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.

The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.

Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.

Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”

“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
 

The phase 2b RISE-SSc study of riociguat

As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.

The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.

In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.

In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
 

An open-label extension trial of lenabasum

In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.

The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.

The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.

The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
 

Evaluating immunosuppressive therapy in SSc

In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.

Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).

Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.

Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”

“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.

“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.

The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.

Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.

However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
 

Moving forward in systemic sclerosis

Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.

“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”

The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.

“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”

Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.

“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.

“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”

The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.

Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an NIH/NIAID Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb.

Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. He also has a patent for a treatment for systemic sclerosis.

Dr. Zheng reported having no disclosures.

[email protected]

CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).

The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.

Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
 

The ACR CRISS

Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).

Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).

A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.

Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.

This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.

Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.

New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
 

The focuSSced study of tocilizumab

For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.

However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.

The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.

Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.

Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.

“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
 

The ASSET trial of abatacept

Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.

Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).

And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.

The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.

Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.

Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”

“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
 

The phase 2b RISE-SSc study of riociguat

As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.

The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.

In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.

In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
 

An open-label extension trial of lenabasum

In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.

The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.

The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.

The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
 

Evaluating immunosuppressive therapy in SSc

In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.

Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).

Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.

Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”

“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.

“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.

The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.

Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.

However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
 

Moving forward in systemic sclerosis

Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.

“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”

The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.

“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”

Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.

“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.

“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”

The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.

Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an NIH/NIAID Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb.

Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. He also has a patent for a treatment for systemic sclerosis.

Dr. Zheng reported having no disclosures.

[email protected]

CHICAGO – At least three phase 3 randomized scleroderma treatment trials presented at the annual meeting of the American College of Rheumatology failed to meet modified Rodnan Skin Score–based primary endpoints, but a different story emerged when data from the trials were analyzed using the novel ACR Composite Response Index in Systemic Sclerosis (CRISS).

The differences highlight the limitations of individual outcome measures like the modified Rodnan Skin Score (mRSS) and underscore the need for new measures that capture the complexity of systemic sclerosis (SSc) and are more sensitive to changes in disease severity, according to Robert Spiera, MD, director of the vasculitis and scleroderma program at the Hospital for Special Surgery in New York.

Such measures are needed to better assess the effects of treatment interventions in scleroderma trials, Dr. Spiera said in an interview.
 

The ACR CRISS

Development of the ACR CRISS was led by Dinesh Khanna, MBBS, a professor of medicine and director of the scleroderma program at the University of Michigan, Ann Arbor. He and his colleagues described the measure in 2016 (Arthritis Rheumatol. 2016 Feb;68[2]:299-311. doi: 10.1002/art.39501).

Its use involves a two-step process of identifying any significant disease worsening or new end-organ damage, and then calculating the probability of patient improvement after 1 year of treatment on a 0- to 1-point scale based on changes from baseline in five variables: the mRSS, percent predicted forced vital capacity (FVC), patient and physician global assessments, and the Health Assessment Questionnaire Disability Index (HAQ-DI).

A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Of note, subjects with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

To devise the CRISS, the investigators compiled 150 patient profiles with standardized clinical outcome elements using patients with diffuse cutaneous systemic sclerosis (dcSSc). The profiles were assessed by 40 scleroderma experts who rated patient improvement or lack thereof over 12 months.

Using the 79% of profiles for which a consensus was reached, the investigators “fit logistic regression models in which the binary outcome referred to whether the patient was improved or not, and the changes in the core set items from baseline to follow-up were entered as covariates,” they explained.

This led to the selection of the five measures included in the final version, which was found to have sensitivity of 0.982 and specificity of 0.931. When evaluated in a previously completed 1-year randomized controlled trial, the index differentiated the effect of methotrexate from the effect of placebo (P = .02), they reported.

Based on these findings, the ACR board of directors granted “provisional” endorsement of the CRISS for use in SSc clinical studies, signifying that it had been quantitatively validated using patient data, but had not undergone validation using an external data set.

New data presented at the 2018 ACR meeting will likely lead to full approval of the measure once the studies validating the measure are published, according to Dr. Spiera.
 

The focuSSced study of tocilizumab

For example, in the phase 3 focuSSced study comparing the interleukin-6 (IL-6) receptor–alpha antibody tocilizumab (Actemra) with placebo in patients with SSc, the primary endpoint of mean change from baseline in mRSS was not met (–6.14 vs. –4.41 points with tocilizumab vs. placebo, respectively; P = .098), Dr. Khanna said during a report of findings from the double-blind portion of the study.

However, when the CRISS was applied and its performance prospectively assessed as an exploratory outcome at week 48 in the focuSSced trial, the differences between the groups were statistically significant. Dr. Khanna reported those findings in a separate presentation at the meeting, noting that they marked the first prospective evaluation of the ACR CRISS in a phase 3 trial in SSc.

The CRISS was applied – using a blinded review of adverse events and serious adverse events to complete step 1 – in all patients who received study treatment, stratified by baseline IL-6 levels.

Of 104 patients in the tocilizumab arm and 106 in the placebo arm, 6 and 13 patients, respectively, had cardio-pulmonary-renal involvement and therefore received a score of 0.

Using the ACR CRISS as a continuous measure, scores favored tocilizumab over placebo at week 48 with a median increase of 0.89 vs. 0.25 points (P = .023), and using the binary form of CRISS, 51% vs. 37% of patients in the treatment and placebo arms achieved the score cutoff of 0.60 or higher at week 48 (P = .035), he said.

“The focuSSced study validates the ACR CRISS endpoint for the first time in an independent prospective clinical trial and highlights the importance of step 1 as an indicator of reduced organ progression during 48 weeks of treatment,” Dr. Khanna concluded.
 

The ASSET trial of abatacept

Dr. Khanna also reported results from the 12-month phase 2 ASSET trial comparing abatacept (Orencia) and placebo in early dcSSc.

Again, the change from baseline in mRSS – the primary endpoint of the study – did not differ significantly with treatment vs. placebo (–6.24 vs. –4.49; P = .28).

And again, as presented separately in a poster session at ACR, application of CRISS at 12 months – a secondary outcome measure in the trial – showed a significant difference between the groups.

The investigators prospectively performed step 1 of the CRISS using a case report form. Of 63 patients with complete data available for relevant outcomes at 12 months, 10 (5 in each group) had cardio-pulmonary-renal involvement and thus were given a score of 0.

Overall, there was evidence of significantly improved CRISS scores in the abatacept group vs. the placebo group (P = .03), he said.

Most of the individual CRISS variables, except HAQ-DI and patient global assessment, had statistically significant correlations with the CRISS, he noted, adding that “although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint.”

“This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials,” he concluded.
 

The phase 2b RISE-SSc study of riociguat

As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.

The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.

In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.

In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.
 

An open-label extension trial of lenabasum

In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.

The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.

The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.

The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.
 

Evaluating immunosuppressive therapy in SSc

In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.

Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).

Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.

Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”

“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.

“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.

The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.

Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.

However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.
 

Moving forward in systemic sclerosis

Indeed, in order to move forward in developing better treatment for SSc, it is important to have the best possible means for assessing the effects of the potential new treatments, Dr. Spiera said.

“The mRSS is a good, reliable outcome measure in terms of intra- and inter-rater reliability, and we know it has meaning in the real world; in a patient with rapidly progressive skin thickening and a skin score that is getting higher and higher, we know they have worse prognosis in terms of function and even survival,” he said. “On the other hand, it’s just one piece of this very complicated story when you’re dealing with patients with systemic sclerosis, some of whom can have important internal organ involvement and not even have skin involvement.”

The main challenge with the skin score is how it performs in clinical trials when it comes to demonstrating whether a drug works, he added.

“This is particularly relevant in an era where our better understanding of the disease has led to candidate therapeutic agents that we have reason to think might work, but where clinical trials haven’t shown a significant difference between the groups using the skin score.”

Conversely, there have been studies in which skin scores improve, but the patient is doing terribly, he noted.

“That patient would not be [shown to be] doing well using the CRISS,” he said, explaining that the complex formula used to determine the CRISS score, which is “heavily weighted toward skin score,” allows for an overall score that is “greater than the sum of its parts.” That is, if a patient is improving in multiple domains indicating that the patient is responding to therapy, more credit is given for each of those parts.

“So my sense, and I think it’s the consensus in the community of clinical investigators, is that the skin score is not adequately sensitive to change in the context of a trial and doesn’t capture the disease holistically enough to be the optimal measure for scleroderma clinical trials,” he said. “We think the CRISS score works better in terms of capturing improvement in the course of a trial, and also in capturing other outcomes that are really, really important to patients and to their physicians, like disability or lung function.”

The hope is that, given the evidence, regulatory agencies will look favorably on the ACR CRISS as an outcome measure in clinical trials moving forward, and that understanding of its use and value will increase across the rheumatology community, he said.

Dr. Spiera has received research grants, consulting fees, and/or other payments from many companies involved in SSc treatments, including Roche/Genentech, which markets tocilizumab, and Corbus Pharmaceuticals, which is developing lenabasum.

Dr. Khanna is a consultant to Roche/Genentech and Bayer, which markets riociguat, and other companies. He has received research grants from Bayer, Bristol-Myers Squibb (which markets abatacept), and Pfizer. The ASSET trial he presented was sponsored by an NIH/NIAID Clinical ACE grant and an investigator-initiated grant by Bristol-Myers Squibb.

Dr. Distler has a consultancy relationship and/or has received research funding from Bayer, Roche/Genentech, and other companies. He also has a patent for a treatment for systemic sclerosis.

Dr. Zheng reported having no disclosures.

[email protected]

SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.

“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.

An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.

Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.

One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.

Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.

Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.

A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.

Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.

Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.

Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.

Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.

Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.

SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.

“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.

An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.

Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.

One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.

Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.

Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.

A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.

Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.

Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.

Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.

Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.

Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.

SAN FRANCISCO – Most years, when it comes to research to treat hepatitis viral infections, hepatitis C has been front and center at the annual meeting of the American Association for the Study of Liver Diseases. But things have changed in the past couple of years, with hepatitis C curative treatment maturing and altering the therapeutic landscape.

“Hepatitis C has been where all the action is, but that’s clearly changed in the last few years,” said Jordan Feld, MD, MPH, who summed up the hepatitis B findings during a wrap-up session on the final day of the conference. Dr. Feld is a clinician-scientist at the Toronto Western Hospital Liver Clinic and the McLaughlin-Rotman Centre for Global Health.

An analysis (Abstract 212) of a mixed North American and Asian cohort of more than 10,000 untreated patients showed just a 1.3% annual clearance rate of surface antigen, with little guidance for risk stratification. “This leaves us really needing new therapies,” said Dr. Feld.

Fortunately, the hepatitis B virus (HBV) life cycle offers various opportunities for therapeutic intervention, including blocking entry, targeting assembly and export of the virus, targeting HBV RNA, and targeting the capsid protein and viral packaging.

One study (Abstract 16) examined a hepatitis B entry inhibitor’s effect on hepatitis D virus (HDV), which requires coinfection with HBV to replicate. A phase 2 clinical trial found that treatment with Myrcludex B alone or in combination with interferon led to a decline in HDV RNA, but the result was most pronounced in patients who received the combination therapy. The combination was also associated with a greater probability of surface antigen decline. “I think that’s really important, that we see this synergistic effect. This is really promising phase 2 data that raises the possibility of curative therapy for this troubling infection,” said Dr. Feld.

Another study (Abstract LB-25) looked at an RNA inhibitor that targets both integrated and covalently closed circular DNA (cccDNA)–derived HBV RNA. The drug was given to 11 HBV patients who were positive for HBeAg (hepatitis B e-antigen) and 13 HBV patients who were HBeAg negative. It had similar effects in reducing HBV surface antigens and other correlated antigens in both groups of patients, and no evidence of a dose-response relationship. “Seeing a similar effect is quite important and suggests that it’s targeting both cccDNA-derived and integrated HBV DNA, and although there were some mild injection reactions, it generally seemed to be safe and pretty well tolerated,” said Dr. Feld.

Further down the life cycle, capsid assembly modulators (CAMs) have the potential to counter HBV by two mechanisms; blocking encapsulation of pregenomic RNA, and degrading capsids, which could prevent the replenishment of cccDNA. The latter effect could be important for achieving a cure, according to Dr. Feld.

A novel CAM, JNJ-6379 (Abstract 74), was tested at three different doses, and was well tolerated at higher doses, but it had limited dose response at the higher dose with respect to HBV DNA suppression. However, it could be that the two CAM mechanisms may require different doses. “These two things are hard to tease apart, and hopefully, we’ll see more data to separate them in the future,” said Dr. Feld.

Another CAM, ABI-HO731 (Abstract 73), had a potent effect on HBV DNA and HBV RNA, showing that it blocks encapsulation of both pregenomic RNA related to reverse transcription and pregenomic RNAs within the capsid. Stopping the medication led to some HBV DNA rebound, though no alanine aminotransferase flares, which Dr. Feld found reassuring. One patient had baseline resistance but was nevertheless able to achieve some suppression on the drug.

Another therapeutic approach used a nucleic acid polymer to block subviral particle release (Abstract 393). The study treated immunosuppressed patients with the polymer alone or in combination with interferon or tenofovir disoproxil, and led to “striking reductions in hepatitis B surface antigen quantities during therapy,” said Dr. Feld. An alanine aminotransferase flair did occur, which may signify an immune response, and it will be important to determine if this is indeed the case, he said. After stopping therapy there was a gain of anti–hepatitis B antibodies, which suggests that functional clearance of surface antigen is occurring.

Researchers also are recruiting the immune system to combat HBV. The novel agent inarigivir is a retinoic acid-inducible gene-1 agonist, which has both a direct antiviral effect and an indirect effect via the intrahepatic innate immune response, which it accomplishes by activating the interferon signaling pathway. It also directly interferes with the interaction between pregenomic RNA and the HBV polymerase, preventing replication. In the ACHIEVE trial, the researchers noted greater reduction in HBV RNA and DNA at higher doses (Abstract 75). “This is certainly an interesting molecule and an interesting proof of concept that you can potentially target HBV using two different pathways, and we’ll be interested to see more data with this approach,” said Dr. Feld.

Dr. Feld wrapped up the discussion of novel therapies with an animal model study (Abstract 77) that suggests future strategies for a cure. In it, the researchers combined a therapeutic vaccine with a stabilized, liver-targeted small interfering RNA to suppress surface antigen. Animals that received only the vaccine saw little benefit, but the combined approach led to viral clearance. The treatment also restored the immune response. “It gives us an inkling that we may need to both reduce the antigen load and stimulate immunity,” said Dr. Feld.

Dr. Feld has consulted for AbbVie, Gilead, ContraVir, MedImmune, and Merck. He has received funding from AbbVie, Gilead, Merck, and Janssen.

Small bowel obstruction (SBO) accounts for 2% of all cases of abdominal pain presenting to the ED and 15% of abdominal pain admissions to surgical units from the ED.^1,2 SBO can be a difficult diagnosis; the most common symptoms include nausea, vomiting, abdominal pain, obstipation, and constipation. The symptomatology depends on multiple factors: the area of the blockage, length of obstruction, and degree of the obstruction (either partial or complete).³ An upper gastrointestinal (GI) blockage classically presents with nausea and vomiting, while a lower GI blockage often presents with abdominal pain, constipation, and obstipation. Complications of obstruction range from significant morbidity—such as bowel strangulation (23%) and sepsis (31%)—to mortality (9%).⁴ ED POCUS allows for rapid and accurate diagnosis of SBO.

CASE

A 60-year-old female with a past medical history of peptic ulcer disease and multiple abdominal surgeries, including umbilical hernia repair, appendectomy, and total abdominal hysterectomy, presented to the ED with an 8-hour history of nausea and vomiting. She reported that her abdomen felt bloated. She had experienced non-bloody, watery stools for the prior 3 weeks. She also reported three to four weeks of epigastric abdominal pain similar to her previous “ulcer pain.” Of note, she was evaluated in GI clinic one day prior to her ED visit for dysphagia, abdominal distention, and diarrhea and was scheduled for an outpatient upper endoscopy. Initial vitals were significant for a heart rate of 100 beats/min. Physical exam was significant for a mildly distended abdomen, tender to palpation at epigastrium without rebound or guarding. Labs showed a white blood cell count of 11.8 K/uL and otherwise unremarkable complete blood count, basic metabolic panel, liver function tests, and lactate measurement. Given the patient’s history of multiple abdominal surgeries and clinical presentation, POCUS was performed to evaluate for SBO. Dilated loops of small bowel were visualized in the lower abdomen gas, suggestive of SBO.

Since the small bowel encompasses a large portion of the abdomen, to fully evaluate for SBO, multiple views are necessary. These include the epigastrium, bilateral colic gutters, and suprapubic regions.5 Use the low-frequency curvilinear transducer to obtain these views, scanning in the transverse and sagittal planes (see Figures 1 and 2). Scan while moving the transducer in columns (ie, “mowing the lawn”), making sure to cover the entire abdomen. To assure that you are evaluating the small bowel, and not the large bowel, look for the characteristic plicae circularis of the small bowel (shown in Figure 3). In children and very slender adults, the high-frequency linear probe may provide enough depth to obtain adequate views.

A fluid-filled small intestinal segment >2.5 cm is consistent with a diagnosis of SBO. Measuring the diameter of the small bowel is both the most sensitive and specific sign; a measurement of greater than 2.5 cm is diagnostic, with a sensitivity of 97% and specificity of 91% (see Figure 4).⁶ This can be somewhat difficult to visualize, as bowel loops are multidirectional and diameters can mistakenly be taken on an indirect cut; to avoid over- or underestimation of bowel diameter, you may want to measure in the short axis using a transverse cross-sectional view of the bowel.

Lack of peristalsis is suggestive of a closed-loop obstruction. However, this finding may be more difficult to visualize, as it requires several continuous minutes of scanning or repeated exams to truly establish absent peristalsis. In prolonged courses of SBO, the bowel wall can measure >3 mm, which suggests necrosis, warranting accelerated surgical intervention. In addition, the detection of extraluminal peritoneal fluid can help determine the severity of the SBO, and small versus large fluid amounts can help determine whether medical or surgical management is warranted (see Figure 5).⁷

DISCUSSION

Increased time to diagnosis of SBO can lead to prolonged patient suffering and greater complication rates. The gold standard for diagnosing SBO—CT with intravenous and oral contrast—can take hours, requiring patients, who are often nauseated, to ingest and tolerate oral contrast. In the past, an “obstructive series” of x-rays would have been used early in the work-up of possible SBO.⁶

Recent literature suggests that POCUS is not only faster, more cost effective, and advantageous (involving no ionizing radiation), but also more accurate than x-rays. Specifically, a meta-analysis by Taylor et al showed pooled estimates for obstructive series x-rays have a sensitivity (Sn) of 75%, a specificity (Sp) of 66%, a positive likelihood ratio (+LR) of 1.6, and a negative likelihood ratio (-LR) of 0.43.¹ On the other hand, pooled results from ED studies of emergency medicine (EM) residents performing POCUS in patients with signs and symptoms suspicious for SBO showed POCUS had a Sn of 97%, Sp of 90%, +LR of 9.5, and a -LR of 0.04.^1,5,8  While detractors point to the operator-dependent nature of POCUS, literature suggests that with EM residents novice to POCUS for SBO (defined as less than 5 previous scans for SBO) were given a 10-minute didactic session and yielded Sn 94%, Sp 81%, +LR 5.0, -LR 0.07.⁵ Unluer et al trained novice EM residents for 6 hours and found them to yield Sn 98%, Sp 95%, +LR 19.5, and -LR 0.02.⁸ Thus, while it is no surprise that those with more training attain better results, both studies show it does not take much time for EM providers to surpass the accuracy of x-rays with POCUS.

CASE CONCLUSION

The findings on POCUS highly suggested the diagnosis of an SBO. A CT scan of the abdomen and pelvis with intravenous and oral contrast was ordered to further evaluate obstruction, transition point, and possible complications, including signs of ischemia per surgical request. CT demonstrated dilated loops of small bowel with transition point in the right lower quadrant, with a small amount of mesenteric fluid consistent with SBO with possible early bowel compromise due to ischemia. General surgery admitted the patient; conservative treatment with serial abdominal exams, nasogastric tube, NPO and bowel rest was ordered. The patient’s diet was gradually advanced, and she was discharged on the eleventh day of hospitalization.

SUMMARY

POCUS is a useful non-invasive tool that can accurately diagnose SBO. POCUS has increased sensitivity and specificity when compared to abdominal X-rays. This bedside imaging will not only give the ED provider rapid diagnostic information but also lead to expedited surgical intervention.

Small bowel obstruction (SBO) accounts for 2% of all cases of abdominal pain presenting to the ED and 15% of abdominal pain admissions to surgical units from the ED.^1,2 SBO can be a difficult diagnosis; the most common symptoms include nausea, vomiting, abdominal pain, obstipation, and constipation. The symptomatology depends on multiple factors: the area of the blockage, length of obstruction, and degree of the obstruction (either partial or complete).³ An upper gastrointestinal (GI) blockage classically presents with nausea and vomiting, while a lower GI blockage often presents with abdominal pain, constipation, and obstipation. Complications of obstruction range from significant morbidity—such as bowel strangulation (23%) and sepsis (31%)—to mortality (9%).⁴ ED POCUS allows for rapid and accurate diagnosis of SBO.

CASE

A 60-year-old female with a past medical history of peptic ulcer disease and multiple abdominal surgeries, including umbilical hernia repair, appendectomy, and total abdominal hysterectomy, presented to the ED with an 8-hour history of nausea and vomiting. She reported that her abdomen felt bloated. She had experienced non-bloody, watery stools for the prior 3 weeks. She also reported three to four weeks of epigastric abdominal pain similar to her previous “ulcer pain.” Of note, she was evaluated in GI clinic one day prior to her ED visit for dysphagia, abdominal distention, and diarrhea and was scheduled for an outpatient upper endoscopy. Initial vitals were significant for a heart rate of 100 beats/min. Physical exam was significant for a mildly distended abdomen, tender to palpation at epigastrium without rebound or guarding. Labs showed a white blood cell count of 11.8 K/uL and otherwise unremarkable complete blood count, basic metabolic panel, liver function tests, and lactate measurement. Given the patient’s history of multiple abdominal surgeries and clinical presentation, POCUS was performed to evaluate for SBO. Dilated loops of small bowel were visualized in the lower abdomen gas, suggestive of SBO.

Since the small bowel encompasses a large portion of the abdomen, to fully evaluate for SBO, multiple views are necessary. These include the epigastrium, bilateral colic gutters, and suprapubic regions.5 Use the low-frequency curvilinear transducer to obtain these views, scanning in the transverse and sagittal planes (see Figures 1 and 2). Scan while moving the transducer in columns (ie, “mowing the lawn”), making sure to cover the entire abdomen. To assure that you are evaluating the small bowel, and not the large bowel, look for the characteristic plicae circularis of the small bowel (shown in Figure 3). In children and very slender adults, the high-frequency linear probe may provide enough depth to obtain adequate views.

A fluid-filled small intestinal segment >2.5 cm is consistent with a diagnosis of SBO. Measuring the diameter of the small bowel is both the most sensitive and specific sign; a measurement of greater than 2.5 cm is diagnostic, with a sensitivity of 97% and specificity of 91% (see Figure 4).⁶ This can be somewhat difficult to visualize, as bowel loops are multidirectional and diameters can mistakenly be taken on an indirect cut; to avoid over- or underestimation of bowel diameter, you may want to measure in the short axis using a transverse cross-sectional view of the bowel.

Lack of peristalsis is suggestive of a closed-loop obstruction. However, this finding may be more difficult to visualize, as it requires several continuous minutes of scanning or repeated exams to truly establish absent peristalsis. In prolonged courses of SBO, the bowel wall can measure >3 mm, which suggests necrosis, warranting accelerated surgical intervention. In addition, the detection of extraluminal peritoneal fluid can help determine the severity of the SBO, and small versus large fluid amounts can help determine whether medical or surgical management is warranted (see Figure 5).⁷

DISCUSSION

Increased time to diagnosis of SBO can lead to prolonged patient suffering and greater complication rates. The gold standard for diagnosing SBO—CT with intravenous and oral contrast—can take hours, requiring patients, who are often nauseated, to ingest and tolerate oral contrast. In the past, an “obstructive series” of x-rays would have been used early in the work-up of possible SBO.⁶

Recent literature suggests that POCUS is not only faster, more cost effective, and advantageous (involving no ionizing radiation), but also more accurate than x-rays. Specifically, a meta-analysis by Taylor et al showed pooled estimates for obstructive series x-rays have a sensitivity (Sn) of 75%, a specificity (Sp) of 66%, a positive likelihood ratio (+LR) of 1.6, and a negative likelihood ratio (-LR) of 0.43.¹ On the other hand, pooled results from ED studies of emergency medicine (EM) residents performing POCUS in patients with signs and symptoms suspicious for SBO showed POCUS had a Sn of 97%, Sp of 90%, +LR of 9.5, and a -LR of 0.04.^1,5,8  While detractors point to the operator-dependent nature of POCUS, literature suggests that with EM residents novice to POCUS for SBO (defined as less than 5 previous scans for SBO) were given a 10-minute didactic session and yielded Sn 94%, Sp 81%, +LR 5.0, -LR 0.07.⁵ Unluer et al trained novice EM residents for 6 hours and found them to yield Sn 98%, Sp 95%, +LR 19.5, and -LR 0.02.⁸ Thus, while it is no surprise that those with more training attain better results, both studies show it does not take much time for EM providers to surpass the accuracy of x-rays with POCUS.

CASE CONCLUSION

The findings on POCUS highly suggested the diagnosis of an SBO. A CT scan of the abdomen and pelvis with intravenous and oral contrast was ordered to further evaluate obstruction, transition point, and possible complications, including signs of ischemia per surgical request. CT demonstrated dilated loops of small bowel with transition point in the right lower quadrant, with a small amount of mesenteric fluid consistent with SBO with possible early bowel compromise due to ischemia. General surgery admitted the patient; conservative treatment with serial abdominal exams, nasogastric tube, NPO and bowel rest was ordered. The patient’s diet was gradually advanced, and she was discharged on the eleventh day of hospitalization.

SUMMARY

POCUS is a useful non-invasive tool that can accurately diagnose SBO. POCUS has increased sensitivity and specificity when compared to abdominal X-rays. This bedside imaging will not only give the ED provider rapid diagnostic information but also lead to expedited surgical intervention.

Small bowel obstruction (SBO) accounts for 2% of all cases of abdominal pain presenting to the ED and 15% of abdominal pain admissions to surgical units from the ED.^1,2 SBO can be a difficult diagnosis; the most common symptoms include nausea, vomiting, abdominal pain, obstipation, and constipation. The symptomatology depends on multiple factors: the area of the blockage, length of obstruction, and degree of the obstruction (either partial or complete).³ An upper gastrointestinal (GI) blockage classically presents with nausea and vomiting, while a lower GI blockage often presents with abdominal pain, constipation, and obstipation. Complications of obstruction range from significant morbidity—such as bowel strangulation (23%) and sepsis (31%)—to mortality (9%).⁴ ED POCUS allows for rapid and accurate diagnosis of SBO.

CASE

A 60-year-old female with a past medical history of peptic ulcer disease and multiple abdominal surgeries, including umbilical hernia repair, appendectomy, and total abdominal hysterectomy, presented to the ED with an 8-hour history of nausea and vomiting. She reported that her abdomen felt bloated. She had experienced non-bloody, watery stools for the prior 3 weeks. She also reported three to four weeks of epigastric abdominal pain similar to her previous “ulcer pain.” Of note, she was evaluated in GI clinic one day prior to her ED visit for dysphagia, abdominal distention, and diarrhea and was scheduled for an outpatient upper endoscopy. Initial vitals were significant for a heart rate of 100 beats/min. Physical exam was significant for a mildly distended abdomen, tender to palpation at epigastrium without rebound or guarding. Labs showed a white blood cell count of 11.8 K/uL and otherwise unremarkable complete blood count, basic metabolic panel, liver function tests, and lactate measurement. Given the patient’s history of multiple abdominal surgeries and clinical presentation, POCUS was performed to evaluate for SBO. Dilated loops of small bowel were visualized in the lower abdomen gas, suggestive of SBO.

Since the small bowel encompasses a large portion of the abdomen, to fully evaluate for SBO, multiple views are necessary. These include the epigastrium, bilateral colic gutters, and suprapubic regions.5 Use the low-frequency curvilinear transducer to obtain these views, scanning in the transverse and sagittal planes (see Figures 1 and 2). Scan while moving the transducer in columns (ie, “mowing the lawn”), making sure to cover the entire abdomen. To assure that you are evaluating the small bowel, and not the large bowel, look for the characteristic plicae circularis of the small bowel (shown in Figure 3). In children and very slender adults, the high-frequency linear probe may provide enough depth to obtain adequate views.

A fluid-filled small intestinal segment >2.5 cm is consistent with a diagnosis of SBO. Measuring the diameter of the small bowel is both the most sensitive and specific sign; a measurement of greater than 2.5 cm is diagnostic, with a sensitivity of 97% and specificity of 91% (see Figure 4).⁶ This can be somewhat difficult to visualize, as bowel loops are multidirectional and diameters can mistakenly be taken on an indirect cut; to avoid over- or underestimation of bowel diameter, you may want to measure in the short axis using a transverse cross-sectional view of the bowel.

Lack of peristalsis is suggestive of a closed-loop obstruction. However, this finding may be more difficult to visualize, as it requires several continuous minutes of scanning or repeated exams to truly establish absent peristalsis. In prolonged courses of SBO, the bowel wall can measure >3 mm, which suggests necrosis, warranting accelerated surgical intervention. In addition, the detection of extraluminal peritoneal fluid can help determine the severity of the SBO, and small versus large fluid amounts can help determine whether medical or surgical management is warranted (see Figure 5).⁷

DISCUSSION

Increased time to diagnosis of SBO can lead to prolonged patient suffering and greater complication rates. The gold standard for diagnosing SBO—CT with intravenous and oral contrast—can take hours, requiring patients, who are often nauseated, to ingest and tolerate oral contrast. In the past, an “obstructive series” of x-rays would have been used early in the work-up of possible SBO.⁶

Recent literature suggests that POCUS is not only faster, more cost effective, and advantageous (involving no ionizing radiation), but also more accurate than x-rays. Specifically, a meta-analysis by Taylor et al showed pooled estimates for obstructive series x-rays have a sensitivity (Sn) of 75%, a specificity (Sp) of 66%, a positive likelihood ratio (+LR) of 1.6, and a negative likelihood ratio (-LR) of 0.43.¹ On the other hand, pooled results from ED studies of emergency medicine (EM) residents performing POCUS in patients with signs and symptoms suspicious for SBO showed POCUS had a Sn of 97%, Sp of 90%, +LR of 9.5, and a -LR of 0.04.^1,5,8  While detractors point to the operator-dependent nature of POCUS, literature suggests that with EM residents novice to POCUS for SBO (defined as less than 5 previous scans for SBO) were given a 10-minute didactic session and yielded Sn 94%, Sp 81%, +LR 5.0, -LR 0.07.⁵ Unluer et al trained novice EM residents for 6 hours and found them to yield Sn 98%, Sp 95%, +LR 19.5, and -LR 0.02.⁸ Thus, while it is no surprise that those with more training attain better results, both studies show it does not take much time for EM providers to surpass the accuracy of x-rays with POCUS.

CASE CONCLUSION

The findings on POCUS highly suggested the diagnosis of an SBO. A CT scan of the abdomen and pelvis with intravenous and oral contrast was ordered to further evaluate obstruction, transition point, and possible complications, including signs of ischemia per surgical request. CT demonstrated dilated loops of small bowel with transition point in the right lower quadrant, with a small amount of mesenteric fluid consistent with SBO with possible early bowel compromise due to ischemia. General surgery admitted the patient; conservative treatment with serial abdominal exams, nasogastric tube, NPO and bowel rest was ordered. The patient’s diet was gradually advanced, and she was discharged on the eleventh day of hospitalization.

SUMMARY

POCUS is a useful non-invasive tool that can accurately diagnose SBO. POCUS has increased sensitivity and specificity when compared to abdominal X-rays. This bedside imaging will not only give the ED provider rapid diagnostic information but also lead to expedited surgical intervention.

Mel C. Anderson, MD, FACP, section chief of hospital medicine for the Veterans Administration of Eastern Colorado, and his hospitalist colleagues share a mission to care for the men and women who served their country in the armed forces and are now being served by the VA.

“That mission binds us together in a deep and impactful way,” he said. “One of the greatest joys of my life has been to dedicate, with the teams I lead, our hearts and minds to serving this population of veterans.”

Approximately 400 hospitalists work nationwide in the VA, the country’s largest integrated health system, typically in groups of about a dozen. Not every VA medical center employs hospitalists; this depends on local tradition and size of the facility. Dr. Anderson was for several years the lone hospitalist at the VA Medical Center in Denver, starting in 2005, and now he heads a group of 17. The Denver facility employs five inpatient teams plus nocturnists, supported by residents, interns, and medical students in training from the University of Colorado at Denver, Aurora, to deliver all of its inpatient medical care.

“We also have an open ICU here. Hospitalists are able to follow their patients across the hospital, and we can make the decision to move them to the ICU,” Dr. Anderson said. The Denver group also established a hospitalist-staffed postdischarge clinic, where patients can reconnect with their hospital team. “It’s not to supplant primary care but to help promote safe transit as the patient moves back to the community,” he said. “We’ve also developed a surgery consult service for orthopedics and other surgical subspecialties.”

The VA’s integrated electronic medical record facilitates communication between hospitalists and primary care physicians, with instant messaging for updating the PCPs on the patient’s hospital stay.

The Denver VA hospitalists value their collegial culture, Dr. Anderson said. “We are invested in our group and in one another and in life-long learning. I often ask my group for their feedback. It’s one of the singular joys of my career to lead such a wonderful group, which has been built up person by person. I hired every single member. As much as their clinical skills and the achievements on their curriculum vitae were important, I also paid attention to their interpersonal communication skills.”

Members of the Denver hospitalist group also share an academic focus and commitment to scholarship and research. Dr. Anderson’s academic emphasis is on how to promote teaching and faculty development through organized bedside rounding and how to orient students to teaching as a potential career path. He is associate program director for medicine residencies at the University of Colorado and leads its Clinician/Educator Pathway.

The VA hospital’s interdisciplinary bedside rounding initiative involves the medicine team – students, residents, attending – and pharmacist, plus the patient’s bedside nurse and nurse care coordinator. “We have worked on fostering an interdisciplinary culture, and we’re very proud of the rounding model we developed here. We all round together at the bedside, and typically that might include 7 or 8 people,” Dr. Anderson explained.

“In planning this program, we used a Rapid Performance Improvement Project team with a nurse, pharmacist, and physical therapist helping us envision how to redesign rounds to overcome the time constraints,” he said. “We altered nurses’ work flow to permit them to join the rounding for their patients, and we moved morning medication administration to 7 a.m., so it wouldn’t get in the way of the rounding. We now audit rates of physician-to-nurse communication on rounds and how often we successfully achieve the nurse’s participation.”¹ This approach has also cut rates of phone pages from nurses to house staff, and substantially increased job satisfaction.
 

What’s different in the VA?

The work of hospitalists in the VA is mostly similar to other hospital settings, but perhaps with more intensity, Dr. Anderson said. There are comorbidities such as higher rates of PTSD, alcohol use disorder, substance abuse, and mental health issues – all of which have an effect over time on patients. But veterans also have different attitudes about, for example, pain.

“When patients are asked to rate their pain on a scale of 0 to 10, for a veteran of a foreign war, 2 out of 10 is not the same as someone else’s 2 out of 10. How do we compensate for that difference?” he said. “And while awareness of PTSD and efforts to mitigate its impact have made incredible gains over the past 15 years, we still see a lot of these issues and their manifestations in social challenges such as homelessness. We are fortunate to have VA outpatient services and homeless veteran programs to help with these issues.”

There is a different paradigm for care at the VA, Dr. Anderson said. “We are a not-for-profit institution with the welfare of veterans as our primary aim. Beyond their health and wellness, that means supporting them in other ways and reaching out into the community. As doctors and nurses we feel a kinship around that mission, although we also have to be stewards of taxpayer dollars. We recognize that the VA is a large and complicated, somewhat inertia-laden organization in which making changes can be very challenging. But there are also opportunities as a national organization to effect changes on a national scale.”

Dr. Anderson chairs the VA’s Hospitalist Field Advisory Committee (HFAC), a group of about eight hospitalists empaneled to advise the system’s Office of Specialty Care Services on clinical policy and program development. They serve 3-year terms and meet monthly by phone and annually in Washington. The HFAC’s last annual meeting occurred in mid-September 2018 in Washington with a focus on developing a hospital medicine annual survey and needs assessment, revisiting strategic goals, and convening multilateral meetings with the chiefs of medicine and emergency medicine FACs.

“Our biggest emphasis is clinical – this includes clinical pathways, best practices for managing PTSD or acute coronary syndrome, and the like. We also share management issues, such as how to configure medical records or arrange night coverage. This is a national conversation to share what some sites have already experienced and learned,” Dr. Anderson said.

“We also have a VA Academic Hospitalist Subcommittee, working together on multisite research studies and on resident education protocols. Because we’re a large system, we’re able to connect with one another and leverage what we’ve learned. I get emails almost every day about research topics from colleagues across the country,” he said. A collaborative website and email distribution list allows doctors to post questions to their peers nationwide.
 

A calling for hospital medicine

Before moving to Denver, Dr. Anderson served as a major in the Air Force Medical Corps and was based at the David Grant US Air Force Medical Center on Travis Air Force Base in California – which is where he did his residency. In the course of a “traditionalist” internal medical training, including 4-month stints on hospital wards in addition to outpatient services, he realized he had a calling for hospital medicine.

In a job at the Providence (R.I.) VA Medical Center, he exclusively practiced outpatient care, but he found that he missed key aspects of inpatient work, such as the intensity of the clinical issues and teaching encounters. “I cold-called the hospital’s chief of medicine and volunteered to start mentoring inpatient residents,” Dr. Anderson said. “That was 17 years ago.”

Another abiding interest derived from Dr. Anderson’s military service is travel medicine. While a physician in the Air Force, he was deployed to Haiti in 1995 and to Nicaragua in 2000, where he treated thousands of patients – both U.S. service personnel and local populations.

“In Haiti, our primary mission was for U.S. troops who were still based there following the 1994 Operation Uphold Democracy intervention, but there were a lot fewer of them, so we mostly kept busy providing care to Haitian nationals,” he said. “That work was eye opening, to say the least,” and led to a professional interest in tropical illnesses. “Since then, I’ve been a visiting professor for the University of Colorado posted to the University of Zimbabwe in Harare in 2012 and 2016.”

What gives Dr. Anderson such joy and enthusiasm for his VA work? “I am a curious lifelong learner. Every day, there are 10 new things I need to learn, whether clinically or operationally in a big hospital system or just the day-to-day realities of leading a group of physicians. I never feel like I’m treading water,” he said. He is also energized by teaching – seeing “the light bulb go on” for the students he is instructing – and by serving as a role model for doctors in training.

“As I contemplate all the simultaneous balls I have in the air, including our recent move into a new hospital building, sometimes I think it is kind of crazy to be doing as much as I do,” he said. “But I also take time away, balancing work versus nonwork.” He spends quality time with his wife of 21 years, 17-year-old daughter, other relatives, and friends, as well as on physical activity, reading books about philosophy, and his hobby of rebuilding motorcycles, which he says offers a kind of meditative calm.

“I also feel a deep sense of service – to patients, colleagues, students, and to the mission of the VA,” Dr. Anderson said. “There is truly something special about caring for the veteran. It’s hard to articulate, but it really keeps us coming back for more. I’ve had vets sing to me, tell jokes, do magic tricks, share their war stories. I’ve had patients open up to me in ways that were both profound and humbling.”
 

References

1. Young E et al. Impact of altered medication administration time on interdisciplinary bedside rounds on academic medical ward. J Nurs Care Qual. 2017 Jul/Sep;32(3):218-225.

Mel C. Anderson, MD, FACP, section chief of hospital medicine for the Veterans Administration of Eastern Colorado, and his hospitalist colleagues share a mission to care for the men and women who served their country in the armed forces and are now being served by the VA.

“That mission binds us together in a deep and impactful way,” he said. “One of the greatest joys of my life has been to dedicate, with the teams I lead, our hearts and minds to serving this population of veterans.”

Approximately 400 hospitalists work nationwide in the VA, the country’s largest integrated health system, typically in groups of about a dozen. Not every VA medical center employs hospitalists; this depends on local tradition and size of the facility. Dr. Anderson was for several years the lone hospitalist at the VA Medical Center in Denver, starting in 2005, and now he heads a group of 17. The Denver facility employs five inpatient teams plus nocturnists, supported by residents, interns, and medical students in training from the University of Colorado at Denver, Aurora, to deliver all of its inpatient medical care.

“We also have an open ICU here. Hospitalists are able to follow their patients across the hospital, and we can make the decision to move them to the ICU,” Dr. Anderson said. The Denver group also established a hospitalist-staffed postdischarge clinic, where patients can reconnect with their hospital team. “It’s not to supplant primary care but to help promote safe transit as the patient moves back to the community,” he said. “We’ve also developed a surgery consult service for orthopedics and other surgical subspecialties.”

The VA’s integrated electronic medical record facilitates communication between hospitalists and primary care physicians, with instant messaging for updating the PCPs on the patient’s hospital stay.

The Denver VA hospitalists value their collegial culture, Dr. Anderson said. “We are invested in our group and in one another and in life-long learning. I often ask my group for their feedback. It’s one of the singular joys of my career to lead such a wonderful group, which has been built up person by person. I hired every single member. As much as their clinical skills and the achievements on their curriculum vitae were important, I also paid attention to their interpersonal communication skills.”

Members of the Denver hospitalist group also share an academic focus and commitment to scholarship and research. Dr. Anderson’s academic emphasis is on how to promote teaching and faculty development through organized bedside rounding and how to orient students to teaching as a potential career path. He is associate program director for medicine residencies at the University of Colorado and leads its Clinician/Educator Pathway.

The VA hospital’s interdisciplinary bedside rounding initiative involves the medicine team – students, residents, attending – and pharmacist, plus the patient’s bedside nurse and nurse care coordinator. “We have worked on fostering an interdisciplinary culture, and we’re very proud of the rounding model we developed here. We all round together at the bedside, and typically that might include 7 or 8 people,” Dr. Anderson explained.

“In planning this program, we used a Rapid Performance Improvement Project team with a nurse, pharmacist, and physical therapist helping us envision how to redesign rounds to overcome the time constraints,” he said. “We altered nurses’ work flow to permit them to join the rounding for their patients, and we moved morning medication administration to 7 a.m., so it wouldn’t get in the way of the rounding. We now audit rates of physician-to-nurse communication on rounds and how often we successfully achieve the nurse’s participation.”¹ This approach has also cut rates of phone pages from nurses to house staff, and substantially increased job satisfaction.
 

What’s different in the VA?

The work of hospitalists in the VA is mostly similar to other hospital settings, but perhaps with more intensity, Dr. Anderson said. There are comorbidities such as higher rates of PTSD, alcohol use disorder, substance abuse, and mental health issues – all of which have an effect over time on patients. But veterans also have different attitudes about, for example, pain.

“When patients are asked to rate their pain on a scale of 0 to 10, for a veteran of a foreign war, 2 out of 10 is not the same as someone else’s 2 out of 10. How do we compensate for that difference?” he said. “And while awareness of PTSD and efforts to mitigate its impact have made incredible gains over the past 15 years, we still see a lot of these issues and their manifestations in social challenges such as homelessness. We are fortunate to have VA outpatient services and homeless veteran programs to help with these issues.”

There is a different paradigm for care at the VA, Dr. Anderson said. “We are a not-for-profit institution with the welfare of veterans as our primary aim. Beyond their health and wellness, that means supporting them in other ways and reaching out into the community. As doctors and nurses we feel a kinship around that mission, although we also have to be stewards of taxpayer dollars. We recognize that the VA is a large and complicated, somewhat inertia-laden organization in which making changes can be very challenging. But there are also opportunities as a national organization to effect changes on a national scale.”

Dr. Anderson chairs the VA’s Hospitalist Field Advisory Committee (HFAC), a group of about eight hospitalists empaneled to advise the system’s Office of Specialty Care Services on clinical policy and program development. They serve 3-year terms and meet monthly by phone and annually in Washington. The HFAC’s last annual meeting occurred in mid-September 2018 in Washington with a focus on developing a hospital medicine annual survey and needs assessment, revisiting strategic goals, and convening multilateral meetings with the chiefs of medicine and emergency medicine FACs.

“Our biggest emphasis is clinical – this includes clinical pathways, best practices for managing PTSD or acute coronary syndrome, and the like. We also share management issues, such as how to configure medical records or arrange night coverage. This is a national conversation to share what some sites have already experienced and learned,” Dr. Anderson said.

“We also have a VA Academic Hospitalist Subcommittee, working together on multisite research studies and on resident education protocols. Because we’re a large system, we’re able to connect with one another and leverage what we’ve learned. I get emails almost every day about research topics from colleagues across the country,” he said. A collaborative website and email distribution list allows doctors to post questions to their peers nationwide.
 

A calling for hospital medicine

Before moving to Denver, Dr. Anderson served as a major in the Air Force Medical Corps and was based at the David Grant US Air Force Medical Center on Travis Air Force Base in California – which is where he did his residency. In the course of a “traditionalist” internal medical training, including 4-month stints on hospital wards in addition to outpatient services, he realized he had a calling for hospital medicine.

In a job at the Providence (R.I.) VA Medical Center, he exclusively practiced outpatient care, but he found that he missed key aspects of inpatient work, such as the intensity of the clinical issues and teaching encounters. “I cold-called the hospital’s chief of medicine and volunteered to start mentoring inpatient residents,” Dr. Anderson said. “That was 17 years ago.”

Another abiding interest derived from Dr. Anderson’s military service is travel medicine. While a physician in the Air Force, he was deployed to Haiti in 1995 and to Nicaragua in 2000, where he treated thousands of patients – both U.S. service personnel and local populations.

“In Haiti, our primary mission was for U.S. troops who were still based there following the 1994 Operation Uphold Democracy intervention, but there were a lot fewer of them, so we mostly kept busy providing care to Haitian nationals,” he said. “That work was eye opening, to say the least,” and led to a professional interest in tropical illnesses. “Since then, I’ve been a visiting professor for the University of Colorado posted to the University of Zimbabwe in Harare in 2012 and 2016.”

What gives Dr. Anderson such joy and enthusiasm for his VA work? “I am a curious lifelong learner. Every day, there are 10 new things I need to learn, whether clinically or operationally in a big hospital system or just the day-to-day realities of leading a group of physicians. I never feel like I’m treading water,” he said. He is also energized by teaching – seeing “the light bulb go on” for the students he is instructing – and by serving as a role model for doctors in training.

“As I contemplate all the simultaneous balls I have in the air, including our recent move into a new hospital building, sometimes I think it is kind of crazy to be doing as much as I do,” he said. “But I also take time away, balancing work versus nonwork.” He spends quality time with his wife of 21 years, 17-year-old daughter, other relatives, and friends, as well as on physical activity, reading books about philosophy, and his hobby of rebuilding motorcycles, which he says offers a kind of meditative calm.

“I also feel a deep sense of service – to patients, colleagues, students, and to the mission of the VA,” Dr. Anderson said. “There is truly something special about caring for the veteran. It’s hard to articulate, but it really keeps us coming back for more. I’ve had vets sing to me, tell jokes, do magic tricks, share their war stories. I’ve had patients open up to me in ways that were both profound and humbling.”
 

References

1. Young E et al. Impact of altered medication administration time on interdisciplinary bedside rounds on academic medical ward. J Nurs Care Qual. 2017 Jul/Sep;32(3):218-225.

Mel C. Anderson, MD, FACP, section chief of hospital medicine for the Veterans Administration of Eastern Colorado, and his hospitalist colleagues share a mission to care for the men and women who served their country in the armed forces and are now being served by the VA.

“That mission binds us together in a deep and impactful way,” he said. “One of the greatest joys of my life has been to dedicate, with the teams I lead, our hearts and minds to serving this population of veterans.”

Approximately 400 hospitalists work nationwide in the VA, the country’s largest integrated health system, typically in groups of about a dozen. Not every VA medical center employs hospitalists; this depends on local tradition and size of the facility. Dr. Anderson was for several years the lone hospitalist at the VA Medical Center in Denver, starting in 2005, and now he heads a group of 17. The Denver facility employs five inpatient teams plus nocturnists, supported by residents, interns, and medical students in training from the University of Colorado at Denver, Aurora, to deliver all of its inpatient medical care.

“We also have an open ICU here. Hospitalists are able to follow their patients across the hospital, and we can make the decision to move them to the ICU,” Dr. Anderson said. The Denver group also established a hospitalist-staffed postdischarge clinic, where patients can reconnect with their hospital team. “It’s not to supplant primary care but to help promote safe transit as the patient moves back to the community,” he said. “We’ve also developed a surgery consult service for orthopedics and other surgical subspecialties.”

The VA’s integrated electronic medical record facilitates communication between hospitalists and primary care physicians, with instant messaging for updating the PCPs on the patient’s hospital stay.

The Denver VA hospitalists value their collegial culture, Dr. Anderson said. “We are invested in our group and in one another and in life-long learning. I often ask my group for their feedback. It’s one of the singular joys of my career to lead such a wonderful group, which has been built up person by person. I hired every single member. As much as their clinical skills and the achievements on their curriculum vitae were important, I also paid attention to their interpersonal communication skills.”

Members of the Denver hospitalist group also share an academic focus and commitment to scholarship and research. Dr. Anderson’s academic emphasis is on how to promote teaching and faculty development through organized bedside rounding and how to orient students to teaching as a potential career path. He is associate program director for medicine residencies at the University of Colorado and leads its Clinician/Educator Pathway.

The VA hospital’s interdisciplinary bedside rounding initiative involves the medicine team – students, residents, attending – and pharmacist, plus the patient’s bedside nurse and nurse care coordinator. “We have worked on fostering an interdisciplinary culture, and we’re very proud of the rounding model we developed here. We all round together at the bedside, and typically that might include 7 or 8 people,” Dr. Anderson explained.

“In planning this program, we used a Rapid Performance Improvement Project team with a nurse, pharmacist, and physical therapist helping us envision how to redesign rounds to overcome the time constraints,” he said. “We altered nurses’ work flow to permit them to join the rounding for their patients, and we moved morning medication administration to 7 a.m., so it wouldn’t get in the way of the rounding. We now audit rates of physician-to-nurse communication on rounds and how often we successfully achieve the nurse’s participation.”¹ This approach has also cut rates of phone pages from nurses to house staff, and substantially increased job satisfaction.
 

What’s different in the VA?

The work of hospitalists in the VA is mostly similar to other hospital settings, but perhaps with more intensity, Dr. Anderson said. There are comorbidities such as higher rates of PTSD, alcohol use disorder, substance abuse, and mental health issues – all of which have an effect over time on patients. But veterans also have different attitudes about, for example, pain.

“When patients are asked to rate their pain on a scale of 0 to 10, for a veteran of a foreign war, 2 out of 10 is not the same as someone else’s 2 out of 10. How do we compensate for that difference?” he said. “And while awareness of PTSD and efforts to mitigate its impact have made incredible gains over the past 15 years, we still see a lot of these issues and their manifestations in social challenges such as homelessness. We are fortunate to have VA outpatient services and homeless veteran programs to help with these issues.”

There is a different paradigm for care at the VA, Dr. Anderson said. “We are a not-for-profit institution with the welfare of veterans as our primary aim. Beyond their health and wellness, that means supporting them in other ways and reaching out into the community. As doctors and nurses we feel a kinship around that mission, although we also have to be stewards of taxpayer dollars. We recognize that the VA is a large and complicated, somewhat inertia-laden organization in which making changes can be very challenging. But there are also opportunities as a national organization to effect changes on a national scale.”

Dr. Anderson chairs the VA’s Hospitalist Field Advisory Committee (HFAC), a group of about eight hospitalists empaneled to advise the system’s Office of Specialty Care Services on clinical policy and program development. They serve 3-year terms and meet monthly by phone and annually in Washington. The HFAC’s last annual meeting occurred in mid-September 2018 in Washington with a focus on developing a hospital medicine annual survey and needs assessment, revisiting strategic goals, and convening multilateral meetings with the chiefs of medicine and emergency medicine FACs.

“Our biggest emphasis is clinical – this includes clinical pathways, best practices for managing PTSD or acute coronary syndrome, and the like. We also share management issues, such as how to configure medical records or arrange night coverage. This is a national conversation to share what some sites have already experienced and learned,” Dr. Anderson said.

“We also have a VA Academic Hospitalist Subcommittee, working together on multisite research studies and on resident education protocols. Because we’re a large system, we’re able to connect with one another and leverage what we’ve learned. I get emails almost every day about research topics from colleagues across the country,” he said. A collaborative website and email distribution list allows doctors to post questions to their peers nationwide.
 

A calling for hospital medicine

Before moving to Denver, Dr. Anderson served as a major in the Air Force Medical Corps and was based at the David Grant US Air Force Medical Center on Travis Air Force Base in California – which is where he did his residency. In the course of a “traditionalist” internal medical training, including 4-month stints on hospital wards in addition to outpatient services, he realized he had a calling for hospital medicine.

In a job at the Providence (R.I.) VA Medical Center, he exclusively practiced outpatient care, but he found that he missed key aspects of inpatient work, such as the intensity of the clinical issues and teaching encounters. “I cold-called the hospital’s chief of medicine and volunteered to start mentoring inpatient residents,” Dr. Anderson said. “That was 17 years ago.”

Another abiding interest derived from Dr. Anderson’s military service is travel medicine. While a physician in the Air Force, he was deployed to Haiti in 1995 and to Nicaragua in 2000, where he treated thousands of patients – both U.S. service personnel and local populations.

“In Haiti, our primary mission was for U.S. troops who were still based there following the 1994 Operation Uphold Democracy intervention, but there were a lot fewer of them, so we mostly kept busy providing care to Haitian nationals,” he said. “That work was eye opening, to say the least,” and led to a professional interest in tropical illnesses. “Since then, I’ve been a visiting professor for the University of Colorado posted to the University of Zimbabwe in Harare in 2012 and 2016.”

What gives Dr. Anderson such joy and enthusiasm for his VA work? “I am a curious lifelong learner. Every day, there are 10 new things I need to learn, whether clinically or operationally in a big hospital system or just the day-to-day realities of leading a group of physicians. I never feel like I’m treading water,” he said. He is also energized by teaching – seeing “the light bulb go on” for the students he is instructing – and by serving as a role model for doctors in training.

“As I contemplate all the simultaneous balls I have in the air, including our recent move into a new hospital building, sometimes I think it is kind of crazy to be doing as much as I do,” he said. “But I also take time away, balancing work versus nonwork.” He spends quality time with his wife of 21 years, 17-year-old daughter, other relatives, and friends, as well as on physical activity, reading books about philosophy, and his hobby of rebuilding motorcycles, which he says offers a kind of meditative calm.

“I also feel a deep sense of service – to patients, colleagues, students, and to the mission of the VA,” Dr. Anderson said. “There is truly something special about caring for the veteran. It’s hard to articulate, but it really keeps us coming back for more. I’ve had vets sing to me, tell jokes, do magic tricks, share their war stories. I’ve had patients open up to me in ways that were both profound and humbling.”
 

References

1. Young E et al. Impact of altered medication administration time on interdisciplinary bedside rounds on academic medical ward. J Nurs Care Qual. 2017 Jul/Sep;32(3):218-225.

A 42-year-old man presented to the ED with a cut to his left forearm from a piece of metal. The patient only complained of pain at the site of injury; he had no numbness or weakness of the left hand. The patient was otherwise in good health, was taking no medications, and was current with his tetanus immunization.

On physical examination, the patient’s vital signs were normal. The emergency physician (EP) documented a vertical laceration of the mid-left forearm on the dorsal aspect, measuring 6 x 2 cm. The wound edges could be easily approximated. The distal motor and sensory exams were normal.

The EP anesthetized the area with local infiltration using 1% plain xylocaine. The EP then picked up a bottle of CaviCide that had been sitting on the counter and sprayed it on the patient’s wound. The patient immediately complained of burning pain, but the EP continued to spray the wound before suturing it closed with 4.0 nylon.

The patient, however, stated the pain was unbearable. He showed the ED manager the bottle of CaviCide and asked if it was an appropriate sterilizing solution for wounds. When informed it was not, the patient demanded the sutures be removed and the wound re-opened and irrigated with an appropriate solution. The EP re-opened the wound, irrigated it with sterile normal saline, and closed it once again using 4.0 nylon. The EP apologized to the patient, admitted that he made a mistake, and discharged the patient home with instructions to have the sutures removed in 10 days.

The patient developed severe pain at the site a few hours later, prompting him to go to a different ED. They applied lidocaine gel to the area and recommended ibuprofen by mouth for pain. The patient was discharged home.

The patient sued the EP, the nurse, and the hospital for negligence. The plaintiff alleged that under no circumstances should CaviCide be used on humans. The plaintiff’s EM expert testified that the error represented gross negligence. The hospital admitted the nurse violated the standard of care for not properly storing the CaviCide. The EP expert for the defense argued the patient did not suffer any new injury or pain, and that his symptoms were due to the laceration. A second defense expert (toxicology) explained that CaviCide is not toxic and that it would only cause short-term irritation. The plaintiff’s counsel asked for $172,800 in damages, explaining that he was requesting $1 per second for the time the patient experienced intense pain.  After deliberating for five hours, the jury found in favor of the defense.

DISCUSSION

Over the years, I have seen variations of this case: hemoccult solution placed in the eye under the impression it was a topical anesthetic, and 1:1000 epinephrine given intravenously (IV) when it was thought to be 1:10,000 concentration.

The way to avoid this mistake is to force yourself to take a good look at whatever medication you are administering to a patient, be it by mouth or IV, on the eye or skin, in a muscle, or up the rectum. Read the name of the medication before giving it. It is fortunate for all involved in this case that no serious or permanent injury occurred.

According to the manufacturer of CaviCide (Metrex), it is a “convenient, ready-to-use, intermediate-level surface disinfectant which is effective against tuberculosis, HBV, HCV, viruses (hydrophilic and lipophilic), bacteria (including MRSA and VRE), and fungi. It is safe for use on non-porous surfaces, and for cleaning environmental and medical device surfaces.” While it sounds great for cleaning surfaces and objects, it is clearly not the right product to spray on a wound.

This accident falls under the general heading of a medication error. This category includes: selecting the wrong medication or dosage; giving the medication at the wrong frequency; administration to the wrong patient or via the wrong route; or failure to monitor the patients’ response to the medication. In the risk management world, it is recommended that providers consistently perform the “five rights” of medication administration: right patient; right drug; right dosage; right time; and right route. This case illustrates the problem of “right drug.” Clearly, CaviCide was not the right drug for this patient. Given different circumstances, the harm could have been significant.

SUMMARY

Fortunately, this is a relatively simple take-home message: know what drug you are giving your patient, always.

A 42-year-old man presented to the ED with a cut to his left forearm from a piece of metal. The patient only complained of pain at the site of injury; he had no numbness or weakness of the left hand. The patient was otherwise in good health, was taking no medications, and was current with his tetanus immunization.

On physical examination, the patient’s vital signs were normal. The emergency physician (EP) documented a vertical laceration of the mid-left forearm on the dorsal aspect, measuring 6 x 2 cm. The wound edges could be easily approximated. The distal motor and sensory exams were normal.

The EP anesthetized the area with local infiltration using 1% plain xylocaine. The EP then picked up a bottle of CaviCide that had been sitting on the counter and sprayed it on the patient’s wound. The patient immediately complained of burning pain, but the EP continued to spray the wound before suturing it closed with 4.0 nylon.

The patient, however, stated the pain was unbearable. He showed the ED manager the bottle of CaviCide and asked if it was an appropriate sterilizing solution for wounds. When informed it was not, the patient demanded the sutures be removed and the wound re-opened and irrigated with an appropriate solution. The EP re-opened the wound, irrigated it with sterile normal saline, and closed it once again using 4.0 nylon. The EP apologized to the patient, admitted that he made a mistake, and discharged the patient home with instructions to have the sutures removed in 10 days.

The patient developed severe pain at the site a few hours later, prompting him to go to a different ED. They applied lidocaine gel to the area and recommended ibuprofen by mouth for pain. The patient was discharged home.

The patient sued the EP, the nurse, and the hospital for negligence. The plaintiff alleged that under no circumstances should CaviCide be used on humans. The plaintiff’s EM expert testified that the error represented gross negligence. The hospital admitted the nurse violated the standard of care for not properly storing the CaviCide. The EP expert for the defense argued the patient did not suffer any new injury or pain, and that his symptoms were due to the laceration. A second defense expert (toxicology) explained that CaviCide is not toxic and that it would only cause short-term irritation. The plaintiff’s counsel asked for $172,800 in damages, explaining that he was requesting $1 per second for the time the patient experienced intense pain.  After deliberating for five hours, the jury found in favor of the defense.

DISCUSSION

Over the years, I have seen variations of this case: hemoccult solution placed in the eye under the impression it was a topical anesthetic, and 1:1000 epinephrine given intravenously (IV) when it was thought to be 1:10,000 concentration.

The way to avoid this mistake is to force yourself to take a good look at whatever medication you are administering to a patient, be it by mouth or IV, on the eye or skin, in a muscle, or up the rectum. Read the name of the medication before giving it. It is fortunate for all involved in this case that no serious or permanent injury occurred.

According to the manufacturer of CaviCide (Metrex), it is a “convenient, ready-to-use, intermediate-level surface disinfectant which is effective against tuberculosis, HBV, HCV, viruses (hydrophilic and lipophilic), bacteria (including MRSA and VRE), and fungi. It is safe for use on non-porous surfaces, and for cleaning environmental and medical device surfaces.” While it sounds great for cleaning surfaces and objects, it is clearly not the right product to spray on a wound.

This accident falls under the general heading of a medication error. This category includes: selecting the wrong medication or dosage; giving the medication at the wrong frequency; administration to the wrong patient or via the wrong route; or failure to monitor the patients’ response to the medication. In the risk management world, it is recommended that providers consistently perform the “five rights” of medication administration: right patient; right drug; right dosage; right time; and right route. This case illustrates the problem of “right drug.” Clearly, CaviCide was not the right drug for this patient. Given different circumstances, the harm could have been significant.

SUMMARY

Fortunately, this is a relatively simple take-home message: know what drug you are giving your patient, always.

A 42-year-old man presented to the ED with a cut to his left forearm from a piece of metal. The patient only complained of pain at the site of injury; he had no numbness or weakness of the left hand. The patient was otherwise in good health, was taking no medications, and was current with his tetanus immunization.

On physical examination, the patient’s vital signs were normal. The emergency physician (EP) documented a vertical laceration of the mid-left forearm on the dorsal aspect, measuring 6 x 2 cm. The wound edges could be easily approximated. The distal motor and sensory exams were normal.

The EP anesthetized the area with local infiltration using 1% plain xylocaine. The EP then picked up a bottle of CaviCide that had been sitting on the counter and sprayed it on the patient’s wound. The patient immediately complained of burning pain, but the EP continued to spray the wound before suturing it closed with 4.0 nylon.

The patient, however, stated the pain was unbearable. He showed the ED manager the bottle of CaviCide and asked if it was an appropriate sterilizing solution for wounds. When informed it was not, the patient demanded the sutures be removed and the wound re-opened and irrigated with an appropriate solution. The EP re-opened the wound, irrigated it with sterile normal saline, and closed it once again using 4.0 nylon. The EP apologized to the patient, admitted that he made a mistake, and discharged the patient home with instructions to have the sutures removed in 10 days.

The patient developed severe pain at the site a few hours later, prompting him to go to a different ED. They applied lidocaine gel to the area and recommended ibuprofen by mouth for pain. The patient was discharged home.

The patient sued the EP, the nurse, and the hospital for negligence. The plaintiff alleged that under no circumstances should CaviCide be used on humans. The plaintiff’s EM expert testified that the error represented gross negligence. The hospital admitted the nurse violated the standard of care for not properly storing the CaviCide. The EP expert for the defense argued the patient did not suffer any new injury or pain, and that his symptoms were due to the laceration. A second defense expert (toxicology) explained that CaviCide is not toxic and that it would only cause short-term irritation. The plaintiff’s counsel asked for $172,800 in damages, explaining that he was requesting $1 per second for the time the patient experienced intense pain.  After deliberating for five hours, the jury found in favor of the defense.

DISCUSSION

Over the years, I have seen variations of this case: hemoccult solution placed in the eye under the impression it was a topical anesthetic, and 1:1000 epinephrine given intravenously (IV) when it was thought to be 1:10,000 concentration.

The way to avoid this mistake is to force yourself to take a good look at whatever medication you are administering to a patient, be it by mouth or IV, on the eye or skin, in a muscle, or up the rectum. Read the name of the medication before giving it. It is fortunate for all involved in this case that no serious or permanent injury occurred.

According to the manufacturer of CaviCide (Metrex), it is a “convenient, ready-to-use, intermediate-level surface disinfectant which is effective against tuberculosis, HBV, HCV, viruses (hydrophilic and lipophilic), bacteria (including MRSA and VRE), and fungi. It is safe for use on non-porous surfaces, and for cleaning environmental and medical device surfaces.” While it sounds great for cleaning surfaces and objects, it is clearly not the right product to spray on a wound.

This accident falls under the general heading of a medication error. This category includes: selecting the wrong medication or dosage; giving the medication at the wrong frequency; administration to the wrong patient or via the wrong route; or failure to monitor the patients’ response to the medication. In the risk management world, it is recommended that providers consistently perform the “five rights” of medication administration: right patient; right drug; right dosage; right time; and right route. This case illustrates the problem of “right drug.” Clearly, CaviCide was not the right drug for this patient. Given different circumstances, the harm could have been significant.

SUMMARY

Fortunately, this is a relatively simple take-home message: know what drug you are giving your patient, always.

A systematic literature review found an inverse association between serum vitamin D levels and severity of atopic dermatitis (AD) in children in the majority of studies, but evidence on whether supplementation can improve symptoms of the condition was inconsistent.

The data on the effect of vitamin D supplementation on AD severity “suggested potential benefit but were conflicting,” concluded Christina M. Huang, MD, of Queen’s University, Kingston, Ontario, and her coinvestigators from the department of dermatology, Hospital for Sick Children, Toronto. They reported the results of their systematic review of 21 studies published between 2008 and 2017, which included quantitative data on serum vitamin D levels or vitamin D supplementation and AD severity in patients aged 18 years or younger, in Pediatrics.

In the review, 16 studies explored the relationship between serum vitamin D status and disease severity (one was a randomized controlled trial; the rest were cohort, cross-sectional, or case control studies) in 1,847 children (average age, 5.6 years). Disease severity was measured with the SCORing Atopic Dermatitis (SCORAD) system. In 10 of the 16 studies, there was a significant inverse association between vitamin D levels and AD severity.

The studies that supported this association generally had larger sample sizes, which, the authors pointed out, suggested they were of higher quality and more reliable. However, the randomized controlled study of 89 children did not find a correlation, although in the study, vitamin D level and AD severity was a secondary outcome.

The randomized controlled trial of vitamin D supplementation used lower SCORAD cut-offs for the different severities of AD, which complicated interpretation the results, “as it may indicate that the severities reported in these articles were exaggerated as compared to other studies,” they wrote.

Six studies – four randomized controlled trials (including the study that was among the 16 studies on vitamin D and severity) and two cohort studies – with 354 participants (average age, 6.8 years) looked at the effects of oral vitamin D supplementation on the severity of AD, although dosage and duration of use varied across the studies. In four of the six studies, there were significant improvement in AD in patients given supplements, but the data were “conflicting,” partly because the largest study showing benefit used a different measure of disease severity, the Eczema Area and Severity Index (EASI), not SCORAD. “The inconsistency of tools used to measure outcomes makes it difficult to compare and understand results,” so the effects of vitamin D supplementation “are controversial and should be interpreted with caution, as certain patient populations may benefit more than others,” the authors wrote.

They also drew attention to previous research suggesting that vitamin D supplementation in the first year of life might actually increase the risk of AD in children. “Therefore, although there is a growing body of evidence supporting the beneficial effects of VD [vitamin D] supplementation, the age at which supplementation is given should be considered carefully.” The authors added that the inconclusive findings “may have been due to confounding factors that were not accounted for, such as age, season, latitude, dose, and duration. It is also possible that the lack of a true effect of VD may be contributing to the inconsistent results. Future large‐scale RCTs with consideration of these factors are needed.”

Funding and conflict of interest disclosures were not included in the study.

SOURCE: Huang C et al. Pediatr Dermatol. 2018;35: 754-60. doi: 10.1111/pde.13639.

A systematic literature review found an inverse association between serum vitamin D levels and severity of atopic dermatitis (AD) in children in the majority of studies, but evidence on whether supplementation can improve symptoms of the condition was inconsistent.

The data on the effect of vitamin D supplementation on AD severity “suggested potential benefit but were conflicting,” concluded Christina M. Huang, MD, of Queen’s University, Kingston, Ontario, and her coinvestigators from the department of dermatology, Hospital for Sick Children, Toronto. They reported the results of their systematic review of 21 studies published between 2008 and 2017, which included quantitative data on serum vitamin D levels or vitamin D supplementation and AD severity in patients aged 18 years or younger, in Pediatrics.

In the review, 16 studies explored the relationship between serum vitamin D status and disease severity (one was a randomized controlled trial; the rest were cohort, cross-sectional, or case control studies) in 1,847 children (average age, 5.6 years). Disease severity was measured with the SCORing Atopic Dermatitis (SCORAD) system. In 10 of the 16 studies, there was a significant inverse association between vitamin D levels and AD severity.

The studies that supported this association generally had larger sample sizes, which, the authors pointed out, suggested they were of higher quality and more reliable. However, the randomized controlled study of 89 children did not find a correlation, although in the study, vitamin D level and AD severity was a secondary outcome.

The randomized controlled trial of vitamin D supplementation used lower SCORAD cut-offs for the different severities of AD, which complicated interpretation the results, “as it may indicate that the severities reported in these articles were exaggerated as compared to other studies,” they wrote.

Six studies – four randomized controlled trials (including the study that was among the 16 studies on vitamin D and severity) and two cohort studies – with 354 participants (average age, 6.8 years) looked at the effects of oral vitamin D supplementation on the severity of AD, although dosage and duration of use varied across the studies. In four of the six studies, there were significant improvement in AD in patients given supplements, but the data were “conflicting,” partly because the largest study showing benefit used a different measure of disease severity, the Eczema Area and Severity Index (EASI), not SCORAD. “The inconsistency of tools used to measure outcomes makes it difficult to compare and understand results,” so the effects of vitamin D supplementation “are controversial and should be interpreted with caution, as certain patient populations may benefit more than others,” the authors wrote.

They also drew attention to previous research suggesting that vitamin D supplementation in the first year of life might actually increase the risk of AD in children. “Therefore, although there is a growing body of evidence supporting the beneficial effects of VD [vitamin D] supplementation, the age at which supplementation is given should be considered carefully.” The authors added that the inconclusive findings “may have been due to confounding factors that were not accounted for, such as age, season, latitude, dose, and duration. It is also possible that the lack of a true effect of VD may be contributing to the inconsistent results. Future large‐scale RCTs with consideration of these factors are needed.”

Funding and conflict of interest disclosures were not included in the study.

SOURCE: Huang C et al. Pediatr Dermatol. 2018;35: 754-60. doi: 10.1111/pde.13639.

A systematic literature review found an inverse association between serum vitamin D levels and severity of atopic dermatitis (AD) in children in the majority of studies, but evidence on whether supplementation can improve symptoms of the condition was inconsistent.

The data on the effect of vitamin D supplementation on AD severity “suggested potential benefit but were conflicting,” concluded Christina M. Huang, MD, of Queen’s University, Kingston, Ontario, and her coinvestigators from the department of dermatology, Hospital for Sick Children, Toronto. They reported the results of their systematic review of 21 studies published between 2008 and 2017, which included quantitative data on serum vitamin D levels or vitamin D supplementation and AD severity in patients aged 18 years or younger, in Pediatrics.

In the review, 16 studies explored the relationship between serum vitamin D status and disease severity (one was a randomized controlled trial; the rest were cohort, cross-sectional, or case control studies) in 1,847 children (average age, 5.6 years). Disease severity was measured with the SCORing Atopic Dermatitis (SCORAD) system. In 10 of the 16 studies, there was a significant inverse association between vitamin D levels and AD severity.

The studies that supported this association generally had larger sample sizes, which, the authors pointed out, suggested they were of higher quality and more reliable. However, the randomized controlled study of 89 children did not find a correlation, although in the study, vitamin D level and AD severity was a secondary outcome.

The randomized controlled trial of vitamin D supplementation used lower SCORAD cut-offs for the different severities of AD, which complicated interpretation the results, “as it may indicate that the severities reported in these articles were exaggerated as compared to other studies,” they wrote.

Six studies – four randomized controlled trials (including the study that was among the 16 studies on vitamin D and severity) and two cohort studies – with 354 participants (average age, 6.8 years) looked at the effects of oral vitamin D supplementation on the severity of AD, although dosage and duration of use varied across the studies. In four of the six studies, there were significant improvement in AD in patients given supplements, but the data were “conflicting,” partly because the largest study showing benefit used a different measure of disease severity, the Eczema Area and Severity Index (EASI), not SCORAD. “The inconsistency of tools used to measure outcomes makes it difficult to compare and understand results,” so the effects of vitamin D supplementation “are controversial and should be interpreted with caution, as certain patient populations may benefit more than others,” the authors wrote.

They also drew attention to previous research suggesting that vitamin D supplementation in the first year of life might actually increase the risk of AD in children. “Therefore, although there is a growing body of evidence supporting the beneficial effects of VD [vitamin D] supplementation, the age at which supplementation is given should be considered carefully.” The authors added that the inconclusive findings “may have been due to confounding factors that were not accounted for, such as age, season, latitude, dose, and duration. It is also possible that the lack of a true effect of VD may be contributing to the inconsistent results. Future large‐scale RCTs with consideration of these factors are needed.”

Funding and conflict of interest disclosures were not included in the study.

SOURCE: Huang C et al. Pediatr Dermatol. 2018;35: 754-60. doi: 10.1111/pde.13639.

The Food and Drug Administration has granted a second “tissue-agnostic” approval for the treatment of cancer, this time to larotrectinib for adult and pediatric patients with solid tumors that harbor a genetic aberration known as an neurotrophic receptor tyrosine kinase (NTRK) fusion.

Specifically, the oral inhibitor of tropomyosin receptor kinase is approved for patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation and have metastatic disease, are likely to experience severe morbidity from surgical resection, have no satisfactory alternative treatments, or have cancer that has progressed following treatment, the FDA said in a press release.

NTRK fusions are found in both children and adults with dozens of different cancer types. The genetic aberration tends to be rare in common cancers and nearly universal in certain uncommon cancers.

Approval of larotrectinib (Vitrakvi) was based on overall response rate and response duration in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across three multicenter, open-label, single-arm clinical trials. The ORR was 75% (95% confidence interval, 61%-85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached, the FDA said.

The most common tumors were salivary gland tumors (22%), soft tissue sarcomas (20%), infantile fibrosarcomas (13%), and thyroid cancers (9%). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization.

Results of the three trials, a phase 1 trial among 8 adult patients (LOXO-TRK-14001), a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 basket trial among 35 adult and adolescent patients (NAVIGATE), were presented at the annual meeting of the American Society of Clinical Oncology in 2017.

The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea, the FDA said.

The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m² orally twice daily (maximum of 100 mg per dose) for pediatric patients.

The approval of larotrectinib follows the approval of pembrolizumab for certain solid tumors with the MSI-H biomarker, as the first approval for the treatment of cancer based on a biomarker rather than the particular body part or organ system affected by the tumor.

The FDA granted the accelerated approval of Vitrakvi to Loxo Oncology and Bayer.

[email protected]

The Food and Drug Administration has granted a second “tissue-agnostic” approval for the treatment of cancer, this time to larotrectinib for adult and pediatric patients with solid tumors that harbor a genetic aberration known as an neurotrophic receptor tyrosine kinase (NTRK) fusion.

Specifically, the oral inhibitor of tropomyosin receptor kinase is approved for patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation and have metastatic disease, are likely to experience severe morbidity from surgical resection, have no satisfactory alternative treatments, or have cancer that has progressed following treatment, the FDA said in a press release.

NTRK fusions are found in both children and adults with dozens of different cancer types. The genetic aberration tends to be rare in common cancers and nearly universal in certain uncommon cancers.

Approval of larotrectinib (Vitrakvi) was based on overall response rate and response duration in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across three multicenter, open-label, single-arm clinical trials. The ORR was 75% (95% confidence interval, 61%-85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached, the FDA said.

The most common tumors were salivary gland tumors (22%), soft tissue sarcomas (20%), infantile fibrosarcomas (13%), and thyroid cancers (9%). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization.

Results of the three trials, a phase 1 trial among 8 adult patients (LOXO-TRK-14001), a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 basket trial among 35 adult and adolescent patients (NAVIGATE), were presented at the annual meeting of the American Society of Clinical Oncology in 2017.

The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea, the FDA said.

The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m² orally twice daily (maximum of 100 mg per dose) for pediatric patients.

The approval of larotrectinib follows the approval of pembrolizumab for certain solid tumors with the MSI-H biomarker, as the first approval for the treatment of cancer based on a biomarker rather than the particular body part or organ system affected by the tumor.

The FDA granted the accelerated approval of Vitrakvi to Loxo Oncology and Bayer.

[email protected]

The Food and Drug Administration has granted a second “tissue-agnostic” approval for the treatment of cancer, this time to larotrectinib for adult and pediatric patients with solid tumors that harbor a genetic aberration known as an neurotrophic receptor tyrosine kinase (NTRK) fusion.

Specifically, the oral inhibitor of tropomyosin receptor kinase is approved for patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation and have metastatic disease, are likely to experience severe morbidity from surgical resection, have no satisfactory alternative treatments, or have cancer that has progressed following treatment, the FDA said in a press release.

NTRK fusions are found in both children and adults with dozens of different cancer types. The genetic aberration tends to be rare in common cancers and nearly universal in certain uncommon cancers.

Approval of larotrectinib (Vitrakvi) was based on overall response rate and response duration in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across three multicenter, open-label, single-arm clinical trials. The ORR was 75% (95% confidence interval, 61%-85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached, the FDA said.

The most common tumors were salivary gland tumors (22%), soft tissue sarcomas (20%), infantile fibrosarcomas (13%), and thyroid cancers (9%). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing or fluorescence in situ hybridization.

Results of the three trials, a phase 1 trial among 8 adult patients (LOXO-TRK-14001), a phase 1/2 trial among 12 pediatric patients (SCOUT), and a phase 2 basket trial among 35 adult and adolescent patients (NAVIGATE), were presented at the annual meeting of the American Society of Clinical Oncology in 2017.

The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea, the FDA said.

The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m² orally twice daily (maximum of 100 mg per dose) for pediatric patients.

The approval of larotrectinib follows the approval of pembrolizumab for certain solid tumors with the MSI-H biomarker, as the first approval for the treatment of cancer based on a biomarker rather than the particular body part or organ system affected by the tumor.

The FDA granted the accelerated approval of Vitrakvi to Loxo Oncology and Bayer.

[email protected]

AUSTIN, TEX. – Providers are no more likely to put an involuntary psychiatric hold on someone who is pregnant than not unless she is using substances, recent research shows.

“This raises a question regarding who psychiatrists consider to be their patients: the mother, the unborn child, or both?” Samuel J. House, MD, of the University of Arkansas, Little Rock, said at the annual meeting of the American Academy of Psychiatry and the Law (AAPL).

Dr. House sent out a survey to members of the AAPL to learn their attitudes toward involuntary psychiatric holds on pregnant women, with and without evidence of substance use, and he presented the results at the meeting.

“We know that the rates of involuntary hospitalizations very widely” across different jurisdictions and practice settings, Dr. House said, but research has shown that age, unmarried status, psychotic symptoms, aggression, and a low level of social function are associated with involuntary commitment. He wanted to explore where pregnancy fit.

Dr. House became interested in clinicians’ perspectives on this issue when he realized how few psychiatric holds he saw among pregnant women during the 4 years he spent at a university hospital’s level 1 trauma center. He included questions about substance use in his survey because of the “recent push to criminalize substance use during pregnancy, mainly in response to the significant impact substance use during pregnancy can have on the fetus or developing child,” he said.

Dr. House received 68 survey responses from AAPL members, most of whom were male with an average age of 47 years. The 7-question survey presented various clinical scenarios and asked what the respondent would do.

The first question concerned being called to the emergency department to evaluate a 28-year-old white woman with clinical signs of depression, history of a suicide attempt, and a mother who had committed suicide when the patient was 15. However, she states during evaluation: “I could never actually kill myself. My family would be too upset, and I would go to hell.”

Two-thirds of respondents (67.6%) said they would admit the woman to an inpatient unit for stabilization, and the others would discharge her with close follow-up.

The second question asked what the clinician would do if the patient declined admission: 41.2% would discharge, and 58.8% would place the woman on a psychiatric hold.

Laws on pregnancy, substance use

Dr. House considered those findings within the context of current laws governing substance use during pregnancy. Currently, 18 states, mostly throughout the South and Midwest, regard drug abuse during pregnancy as child abuse, with prosecution usually requiring detection of the substance at birth or during pregnancy, or evidence of risk to the child’s health.

Tennessee is unique in considering substance abuse in pregnancy assault if the child is born with dependence or other harm from the drug use. Women in Minnesota, South Dakota, and Wisconsin can be subject to civil commitment, including required inpatient drug treatment, for substance abuse during pregnancy (Am J Psychiatry. 2016 Nov 1;173[11]:1077-80).

Mandatory reporting laws for suspected substance abuse during pregnancy exist in 15 states, mostly in the Southwest, northern Midwest, and states around the District of Columbia. And four states – Kentucky, Iowa, Minnesota, and North Dakota – require pregnant women suspected of substance abuse to be tested.

Yet, most major relevant medical associations oppose criminalization of substance use during pregnancy, including the American Psychiatric Association, the American Academy of Addiction Psychiatry, the American Medical Association, and the American College of Obstetricians and Gynecologists.

“They are generally for increasing access for people, like voluntary screening, but against criminalization because it creates a barrier to accessing prenatal care,” Dr. House explained.

Aside from the question of whom psychiatrists consider their patients – the woman, her fetus, or both – the results raise another question, Dr. House said: “While studies have shown that criminalizing substance use during pregnancy discourages mothers from seeking prenatal care, does the threat of an involuntary psychiatric admission have a similar consequence?” That’s a question for further research.

No external funding was used. Dr. House was a clinical investigator without compensation for Janssen Pharmaceuticals from 2015 to 2017.

AUSTIN, TEX. – Providers are no more likely to put an involuntary psychiatric hold on someone who is pregnant than not unless she is using substances, recent research shows.

“This raises a question regarding who psychiatrists consider to be their patients: the mother, the unborn child, or both?” Samuel J. House, MD, of the University of Arkansas, Little Rock, said at the annual meeting of the American Academy of Psychiatry and the Law (AAPL).

Dr. House sent out a survey to members of the AAPL to learn their attitudes toward involuntary psychiatric holds on pregnant women, with and without evidence of substance use, and he presented the results at the meeting.

“We know that the rates of involuntary hospitalizations very widely” across different jurisdictions and practice settings, Dr. House said, but research has shown that age, unmarried status, psychotic symptoms, aggression, and a low level of social function are associated with involuntary commitment. He wanted to explore where pregnancy fit.

Dr. House became interested in clinicians’ perspectives on this issue when he realized how few psychiatric holds he saw among pregnant women during the 4 years he spent at a university hospital’s level 1 trauma center. He included questions about substance use in his survey because of the “recent push to criminalize substance use during pregnancy, mainly in response to the significant impact substance use during pregnancy can have on the fetus or developing child,” he said.

Dr. House received 68 survey responses from AAPL members, most of whom were male with an average age of 47 years. The 7-question survey presented various clinical scenarios and asked what the respondent would do.

The first question concerned being called to the emergency department to evaluate a 28-year-old white woman with clinical signs of depression, history of a suicide attempt, and a mother who had committed suicide when the patient was 15. However, she states during evaluation: “I could never actually kill myself. My family would be too upset, and I would go to hell.”

Two-thirds of respondents (67.6%) said they would admit the woman to an inpatient unit for stabilization, and the others would discharge her with close follow-up.

The second question asked what the clinician would do if the patient declined admission: 41.2% would discharge, and 58.8% would place the woman on a psychiatric hold.

Laws on pregnancy, substance use

Dr. House considered those findings within the context of current laws governing substance use during pregnancy. Currently, 18 states, mostly throughout the South and Midwest, regard drug abuse during pregnancy as child abuse, with prosecution usually requiring detection of the substance at birth or during pregnancy, or evidence of risk to the child’s health.

Tennessee is unique in considering substance abuse in pregnancy assault if the child is born with dependence or other harm from the drug use. Women in Minnesota, South Dakota, and Wisconsin can be subject to civil commitment, including required inpatient drug treatment, for substance abuse during pregnancy (Am J Psychiatry. 2016 Nov 1;173[11]:1077-80).

Mandatory reporting laws for suspected substance abuse during pregnancy exist in 15 states, mostly in the Southwest, northern Midwest, and states around the District of Columbia. And four states – Kentucky, Iowa, Minnesota, and North Dakota – require pregnant women suspected of substance abuse to be tested.

Yet, most major relevant medical associations oppose criminalization of substance use during pregnancy, including the American Psychiatric Association, the American Academy of Addiction Psychiatry, the American Medical Association, and the American College of Obstetricians and Gynecologists.

“They are generally for increasing access for people, like voluntary screening, but against criminalization because it creates a barrier to accessing prenatal care,” Dr. House explained.

Aside from the question of whom psychiatrists consider their patients – the woman, her fetus, or both – the results raise another question, Dr. House said: “While studies have shown that criminalizing substance use during pregnancy discourages mothers from seeking prenatal care, does the threat of an involuntary psychiatric admission have a similar consequence?” That’s a question for further research.

No external funding was used. Dr. House was a clinical investigator without compensation for Janssen Pharmaceuticals from 2015 to 2017.

AUSTIN, TEX. – Providers are no more likely to put an involuntary psychiatric hold on someone who is pregnant than not unless she is using substances, recent research shows.

“This raises a question regarding who psychiatrists consider to be their patients: the mother, the unborn child, or both?” Samuel J. House, MD, of the University of Arkansas, Little Rock, said at the annual meeting of the American Academy of Psychiatry and the Law (AAPL).

Dr. House sent out a survey to members of the AAPL to learn their attitudes toward involuntary psychiatric holds on pregnant women, with and without evidence of substance use, and he presented the results at the meeting.

“We know that the rates of involuntary hospitalizations very widely” across different jurisdictions and practice settings, Dr. House said, but research has shown that age, unmarried status, psychotic symptoms, aggression, and a low level of social function are associated with involuntary commitment. He wanted to explore where pregnancy fit.

Dr. House became interested in clinicians’ perspectives on this issue when he realized how few psychiatric holds he saw among pregnant women during the 4 years he spent at a university hospital’s level 1 trauma center. He included questions about substance use in his survey because of the “recent push to criminalize substance use during pregnancy, mainly in response to the significant impact substance use during pregnancy can have on the fetus or developing child,” he said.

Dr. House received 68 survey responses from AAPL members, most of whom were male with an average age of 47 years. The 7-question survey presented various clinical scenarios and asked what the respondent would do.

The first question concerned being called to the emergency department to evaluate a 28-year-old white woman with clinical signs of depression, history of a suicide attempt, and a mother who had committed suicide when the patient was 15. However, she states during evaluation: “I could never actually kill myself. My family would be too upset, and I would go to hell.”

Two-thirds of respondents (67.6%) said they would admit the woman to an inpatient unit for stabilization, and the others would discharge her with close follow-up.

The second question asked what the clinician would do if the patient declined admission: 41.2% would discharge, and 58.8% would place the woman on a psychiatric hold.

Laws on pregnancy, substance use

Dr. House considered those findings within the context of current laws governing substance use during pregnancy. Currently, 18 states, mostly throughout the South and Midwest, regard drug abuse during pregnancy as child abuse, with prosecution usually requiring detection of the substance at birth or during pregnancy, or evidence of risk to the child’s health.

Tennessee is unique in considering substance abuse in pregnancy assault if the child is born with dependence or other harm from the drug use. Women in Minnesota, South Dakota, and Wisconsin can be subject to civil commitment, including required inpatient drug treatment, for substance abuse during pregnancy (Am J Psychiatry. 2016 Nov 1;173[11]:1077-80).

Mandatory reporting laws for suspected substance abuse during pregnancy exist in 15 states, mostly in the Southwest, northern Midwest, and states around the District of Columbia. And four states – Kentucky, Iowa, Minnesota, and North Dakota – require pregnant women suspected of substance abuse to be tested.

Yet, most major relevant medical associations oppose criminalization of substance use during pregnancy, including the American Psychiatric Association, the American Academy of Addiction Psychiatry, the American Medical Association, and the American College of Obstetricians and Gynecologists.

“They are generally for increasing access for people, like voluntary screening, but against criminalization because it creates a barrier to accessing prenatal care,” Dr. House explained.

Aside from the question of whom psychiatrists consider their patients – the woman, her fetus, or both – the results raise another question, Dr. House said: “While studies have shown that criminalizing substance use during pregnancy discourages mothers from seeking prenatal care, does the threat of an involuntary psychiatric admission have a similar consequence?” That’s a question for further research.

No external funding was used. Dr. House was a clinical investigator without compensation for Janssen Pharmaceuticals from 2015 to 2017.