User login
Protein may be therapeutic target for AML
and Matt McCormack, PhD
Photo courtesy of the
Walter and Eliza Hall
Institute of Medical Research
Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).
Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.
Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.
“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”
Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.
However, Hhex was not required for normal myelopoiesis.
“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.
“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”
Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.
They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.
“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.
“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”
Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.
“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.
“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.” 
and Matt McCormack, PhD
Photo courtesy of the
Walter and Eliza Hall
Institute of Medical Research
Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).
Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.
Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.
“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”
Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.
However, Hhex was not required for normal myelopoiesis.
“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.
“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”
Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.
They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.
“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.
“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”
Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.
“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.
“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.”
and Matt McCormack, PhD
Photo courtesy of the
Walter and Eliza Hall
Institute of Medical Research
Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).
Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.
Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.
“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”
Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.
However, Hhex was not required for normal myelopoiesis.
“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.
“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”
Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.
They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.
“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.
“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”
Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.
“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.
“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.”
Poor Hospital Mobility
Low mobility is common in hospitalized older patients, and an independent predictor of poor functional outcomes.[1, 2, 3, 4] Few studies have included younger patients, but care models that support early mobility may reduce functional decline, enhance recovery, and reduce length of stay in older and mixed‐age populations.[5, 6] Barriers to mobility are complex and include patient symptoms and tethers, health provider behavior, team communication, and leadership, device availability, and environmental factors.[7, 8, 9, 10, 11] These contextual factors may differ even within a hospital between patient groups and ward settings. Simple measures to quantify mobility patterns would help address these barriers by providing opportunities for audit and feedback. Although accelerometry is the gold standard method for research, it requires equipment, analysis skills, and patient consent, which limits application in clinical practice. Behavioral mapping is a systematic method of observation developed in stroke patients, which is simple, objective, and requires no direct patient or staff participation,[12] and physical activity levels estimated from behavioral mapping are similar to those identified by accelerometry.[3, 13, 14] In the context of a phased quality‐improvement project aiming to reduce functional decline,[15] we undertook a cross‐sectional audit of mobility on 3 different wards using behavioral mapping, and examined differences among wards and between older (aged 65 years or more) and younger patients.
METHODS
This prospective observational study used cross‐sectional sampling from a 26‐bed general medical ward, a 30‐bed oncology ward, and a 24‐bed vascular surgical ward in a 900‐bed tertiary teaching hospital in Brisbane, Australia. Sampling was undertaken during 4 observation periods (2 mornings [10001400] and 2 afternoons [1400‐1800]) within 10 days in May 2013. All patients on each ward for each period were observed unless they were receiving end‐of‐life care. Structured observations were undertaken using behavioral mapping protocols similar to those previously described in stroke and general medical patients,[12, 13] with each patient room visited in the same sequence. Participants in each room were observed for a 2‐minute period (up to 4 participants could be observed concurrently in shared rooms) before moving to the next room, and the sequence was repeated in the same order for the whole 4‐hour period, with a single 15‐minute break. Depending on ward size and layout, this provided 12 to 17 observations per participant for each 4‐hour period (each individual observed every 1218 minutes). Observations were undertaken by 4 trained physiotherapy student observers using a predetermined set of mutually exclusive levels (lying in bed, sitting in or on the bed, sitting on a chair, standing, actively wheeling, or walking). The study was approved by the Royal Brisbane and Women's Hospital Human Research Ethics Committee as part of a quality‐improvement activity, and individual consent was not required. No clinical data except age and gender were collected for participants. The nurse unit manager for each ward was introduced to the observers and aware that observations were being conducted.
Patients who were observed for less than one‐half of an observation period were excluded so that all participants contributed at least 2 hours of observational data, up to a maximum of 16 hours. The number of valid observations for each participant (excluding time off ward or behind curtains if the level was not apparent) was calculated and used to derive the proportion of valid observations spent at each level for each participant. The proportion of observations at each level was summarized across all participants using frequency distributions and summary statistics. For ease of presentation, mean percentage of observed time in each activity was presented. However, as data were not normally distributed, statistical comparisons were undertaken using the Kruskal‐Wallis test, comparing the distribution of time spent upright (standing, walking, or actively wheeling) between groups (age group and ward). Interaction between age and ward effects was sought using generalized linear modeling.
RESULTS
Valid observations (at least 2 hours in 1 or more observation period) were available for 132 patients (48 medical, 50 oncology, and 34 surgery). Of these, 67 (51 %) were aged 65 years (54% medical, 44% oncology, 56% surgery) and 62 (47%) were male. There were a total of 3891 observations of location (median, 30 per patient; range, 965). Participants were observed in the bedded area 85.1% of observations, with 3.1% in the bathroom, 3.2% in the hallway or patient lounge, and 8.6% off ward. Allowing for time off ward and behind curtains, when observers could not be sure of their activity level, 3272 valid observations were available for physical activity.
More than half of the observed time (mean 57.4%) was spent lying in bed, 33.6% sitting on the bed or chair, and 9.0% standing, walking, or wheeling. Across all observation periods, 39/132 (29.5%) participants were never observed to be standing, walking or wheeling, and 7.6% were in bed at all observations. Comparing older and younger patients (Table 1), there was no difference in the time spent in active upright postures (median, 6.1% in older vs 7.4% in younger; P = 0.30). Table 2 summarizes descriptive data for the different wards. In the medical and surgical wards, 84% of the time was spend in or on the bed, and only 16% of the time was spent sitting in a chair or in active upright postures. Surgical patients, in particular, spent two‐thirds of observation time lying flat in bed, whereas medical patients spent more time sitting up on the bed. On statistical testing, time spent standing/walking/wheeling was significantly lower on the surgical ward (median, 4%; interquartile range [IQR], 010 for surgery; median, 7%; IQR, 013 for medical; and median, 10%; IQR 317 for oncology; P = 0.015). This was also reflected in a higher proportion of surgical patients never seen in an active upright position (44.1% compared to 27.1% medical and 22.0% oncology). Multivariate modeling showed no significant interaction between age and ward.
| All Ages, n = 132, Median Observations 29.5, Range 665* | Aged 65 Years, n = 61, Median Observations 30, Range 665 | Aged 65 Years, n = 67, Median Observations 27, Range 665 | |
|---|---|---|---|
| |||
| Location | |||
| Bedroom | 85.1 (13.3) | 84.6 (13.4) | 85.5 (12.9) |
| Bathroom | 3.0 (4.0) | 2.6 (3.9) | 3.4 (4.1) |
| Hall | 2.9 (4.6) | 3.4 (5.4) | 2.7 (4.0) |
| Lounge | 0.3 (1.9) | 0 | 0.6 (2.7) |
| Off ward/other | 8.6 (11.6) | 9.3 (11.4) | 7.8 (11.1) |
| Physical activity | |||
| Lie in bed | 57.4 (30.0) | 59.4 (29.4) | 55.5 (31.6) |
| Sit on bed | 21.0 (23.2) | 16.9 (19.9) | 24.7 (25.7) |
| Sit on chair | 12.6 (22.9) | 14.0 (25.6) | 11.9 (20.9) |
| Stand/walk/wheel | 9.0 (9.3) | 9.6 (9.6) | 8.0 (8.5) |
| Medical, n = 48, Median Observations 30, Range 759 | Oncology, n = 50, Median Observations 25, Range 652 | Surgical, n = 34, Median Observations 31, Range 1765 | |
|---|---|---|---|
| Location | |||
| Bedroom | 89.1 (11.4) | 81.3 (13.6) | 85.3 (14.1) |
| Bathroom | 2.8 (4.1) | 3.1 (3.8) | 3.1 (4.2) |
| Hall | 1.5 (2.5) | 5.3 (6.1) | 1.5 (2.7) |
| Lounge | 0.5 (2.0) | 0.4 (2.5) | 0 |
| Off ward/other | 6.2 (10.2) | 10.0 (11.9) | 10.1 (12.6) |
| Physical activity | |||
| Lie in bed | 53.3 (31.4) | 56.1 (30.2) | 65.1 (27.0) |
| Sit on bed | 30.3 (29.5) | 13.4 (16.1) | 19.0 (17.0) |
| Sit on chair | 8.2 (14.7) | 19.1 (29.1) | 9.3 (20.4) |
| Stand/walk/wheel | 8.2 (8.4) | 11.4 (9.7) | 6.5 (9.4) |
DISCUSSION
This observational cross‐sectional study extends previous observations of hospital inpatients to include a wider variety of patient types and ages. Observing 132 patients on medical, surgical, and oncology wards for up to 16 hours of weekday time, we found that patients spent only 9% in active upright postures, with significantly lower mobility on the surgical ward but no significant differences between older and younger patients.
Previous studies in older general medical patients using behavioral mapping[13] or accelerometers[2, 3] have shown 71% to 83% of time spent in bed, and 4% spent standing or walking, similar to our findings, although methodological differences between studies (eg, patient selection and time windows) caution against direct comparison. We identified different levels of physical activity on the surgical, medical, and oncology wards. This may reflect differences in patient case‐mix, ward environment, and/or ward culture. The medical and oncology wards each have a patient lounge, providing a potential walking destination, although only a small amount of patients' time was observed in these areas, suggesting that they may not fulfil their purpose. The oncology ward has a well developed wellness focus. The oncology and medical wards were actively involved in a quality‐improvement intervention to improve early patient mobility at the time of the audit,[15] whereas the surgical ward was at the precommencement (information gathering) stage. The data collected within this audit have formed part of the feedback cycle for staff involved in the improvement intervention. Repeat measurement will be undertaken on the surgical ward to help evaluate the impact of the intervention, and serial measurement will be undertaken in future participating wards to investigate the responsiveness of this measurement method.
Although the literature has focused on poor mobility in hospitalized elders, we did not find any better mobility in younger patients, suggesting that barriers to mobility are not confined to the elderly. Whereas individualized mobility assessment and support may be more important in the elderly,[16] addressing cultural and environmental issues such as promoting accountability for early ambulation, providing patients and families with permission and encouragement to ambulate, and ensuring accessible walking destinations may benefit patients of all ages.
Behavioral mapping has strengths and weaknesses compared to other methods such as accelerometry or patient/nurse report. Observations are conducted by an independent observer not involved in care and include all ward inpatients, providing a generalizable sample, as the observation protocol does not pose a participation burden for patient or ward staff. However, the cross‐sectional nature may oversample longer‐stay patients, the intermittent observation protocol tends to overestimate time spent upright,[14] the labor‐intensive nature of observations means choosing a limited time window (in our case 10001800), and the minimum time and observation frequency to generate reliable data remain uncertain. Further studies examining reliability, validity, and responsiveness would support the utility of this method for quality improvement.
In summary, this study shows that mobility is limited in older and younger adult inpatients across a range of inpatient wards, and that physical activity practices vary among wards. Interventions to enhance hospital mobility should include patients of all ages, and need to be tailored to local mobility practices, barriers, and enablers.
Acknowledgements
The authors thank the staff of wards 6AS, 9BN, and 7BW for participating in this project.
Disclosure: Nothing to report.
- , , . Prevalence and outcomes of low mobility in hospitalized older patients. J Am Geriatr Soc. 2004;52(8):1263–1270.
- , , , . The underrecognized epidemic of low mobility during hospitalization of older adults. J Am Geriatr Soc. 2009;57:1660–1665.
- , , , et al. Twenty‐four‐hour mobility during acute hospitalization in older medical patients. J Gerontol A Biol Sci Med Sci. 2013;68(3):331–337.
- , , , , , . Low mobility during hospitalization and functional decline in older adults. J Am Geriatr Soc. 2011;59(2):266–273.
- , , . Exercising body and mind: an integrated approach to functional independence. J Am Geriatr Soc. 2008;56:630–635.
- , , , , . Early mobilization of patients hospitalized with community‐acquired pneumonia. Chest. 2003;124(124):883–889.
- , , . Nursing staff perceptions of physical function in hospitalized older adults. App Nurs Res. 2011;24:215–222.
- , , , , . Barriers to mobility during hospitalization from the perspectives of older patients and their nurses and physicians. J Hosp Med. 2007;2:305–313.
- , . How nurses decide to ambulate hospitalized older adults: development of a conceptual model. Gerontologist. 2011;51(6):786–797.
- , , , . Barriers to early mobility of hospitalized general medicine patients. Survey development and validation. Am J Phys Med Rehabil. 2015;94:304–312.
- , . Attitudes and expectations regarding exercise in the hospital of hospitalized older adults: a qualitative study. J Am Geriatr Soc. 2012;60:713–718.
- , , , . Inactive and alone. Physical activity within the first 14 days of acute stroke unit care. Stroke. 2004;35:1005–1009.
- , , . Activity level of hospital medical inpatients: an observational study. Arch Gerontol Geriatr. 2012;55:417–421.
- , , , . Measuring activity levels at an acute stroke ward: comparing observations to a device. Biomed Res Int. 2013;2013:460482.
- , , . Eat walk engage: an interdisciplinary collaborative model to improve care of hospitalized elders. Am J Med Qual. 2015;30(1):5–13.
- , , . Hospitalization‐associated disability. “She was probably able to ambulate, but I'm not sure”. JAMA. 2011;306(16):1782–1793.
Low mobility is common in hospitalized older patients, and an independent predictor of poor functional outcomes.[1, 2, 3, 4] Few studies have included younger patients, but care models that support early mobility may reduce functional decline, enhance recovery, and reduce length of stay in older and mixed‐age populations.[5, 6] Barriers to mobility are complex and include patient symptoms and tethers, health provider behavior, team communication, and leadership, device availability, and environmental factors.[7, 8, 9, 10, 11] These contextual factors may differ even within a hospital between patient groups and ward settings. Simple measures to quantify mobility patterns would help address these barriers by providing opportunities for audit and feedback. Although accelerometry is the gold standard method for research, it requires equipment, analysis skills, and patient consent, which limits application in clinical practice. Behavioral mapping is a systematic method of observation developed in stroke patients, which is simple, objective, and requires no direct patient or staff participation,[12] and physical activity levels estimated from behavioral mapping are similar to those identified by accelerometry.[3, 13, 14] In the context of a phased quality‐improvement project aiming to reduce functional decline,[15] we undertook a cross‐sectional audit of mobility on 3 different wards using behavioral mapping, and examined differences among wards and between older (aged 65 years or more) and younger patients.
METHODS
This prospective observational study used cross‐sectional sampling from a 26‐bed general medical ward, a 30‐bed oncology ward, and a 24‐bed vascular surgical ward in a 900‐bed tertiary teaching hospital in Brisbane, Australia. Sampling was undertaken during 4 observation periods (2 mornings [10001400] and 2 afternoons [1400‐1800]) within 10 days in May 2013. All patients on each ward for each period were observed unless they were receiving end‐of‐life care. Structured observations were undertaken using behavioral mapping protocols similar to those previously described in stroke and general medical patients,[12, 13] with each patient room visited in the same sequence. Participants in each room were observed for a 2‐minute period (up to 4 participants could be observed concurrently in shared rooms) before moving to the next room, and the sequence was repeated in the same order for the whole 4‐hour period, with a single 15‐minute break. Depending on ward size and layout, this provided 12 to 17 observations per participant for each 4‐hour period (each individual observed every 1218 minutes). Observations were undertaken by 4 trained physiotherapy student observers using a predetermined set of mutually exclusive levels (lying in bed, sitting in or on the bed, sitting on a chair, standing, actively wheeling, or walking). The study was approved by the Royal Brisbane and Women's Hospital Human Research Ethics Committee as part of a quality‐improvement activity, and individual consent was not required. No clinical data except age and gender were collected for participants. The nurse unit manager for each ward was introduced to the observers and aware that observations were being conducted.
Patients who were observed for less than one‐half of an observation period were excluded so that all participants contributed at least 2 hours of observational data, up to a maximum of 16 hours. The number of valid observations for each participant (excluding time off ward or behind curtains if the level was not apparent) was calculated and used to derive the proportion of valid observations spent at each level for each participant. The proportion of observations at each level was summarized across all participants using frequency distributions and summary statistics. For ease of presentation, mean percentage of observed time in each activity was presented. However, as data were not normally distributed, statistical comparisons were undertaken using the Kruskal‐Wallis test, comparing the distribution of time spent upright (standing, walking, or actively wheeling) between groups (age group and ward). Interaction between age and ward effects was sought using generalized linear modeling.
RESULTS
Valid observations (at least 2 hours in 1 or more observation period) were available for 132 patients (48 medical, 50 oncology, and 34 surgery). Of these, 67 (51 %) were aged 65 years (54% medical, 44% oncology, 56% surgery) and 62 (47%) were male. There were a total of 3891 observations of location (median, 30 per patient; range, 965). Participants were observed in the bedded area 85.1% of observations, with 3.1% in the bathroom, 3.2% in the hallway or patient lounge, and 8.6% off ward. Allowing for time off ward and behind curtains, when observers could not be sure of their activity level, 3272 valid observations were available for physical activity.
More than half of the observed time (mean 57.4%) was spent lying in bed, 33.6% sitting on the bed or chair, and 9.0% standing, walking, or wheeling. Across all observation periods, 39/132 (29.5%) participants were never observed to be standing, walking or wheeling, and 7.6% were in bed at all observations. Comparing older and younger patients (Table 1), there was no difference in the time spent in active upright postures (median, 6.1% in older vs 7.4% in younger; P = 0.30). Table 2 summarizes descriptive data for the different wards. In the medical and surgical wards, 84% of the time was spend in or on the bed, and only 16% of the time was spent sitting in a chair or in active upright postures. Surgical patients, in particular, spent two‐thirds of observation time lying flat in bed, whereas medical patients spent more time sitting up on the bed. On statistical testing, time spent standing/walking/wheeling was significantly lower on the surgical ward (median, 4%; interquartile range [IQR], 010 for surgery; median, 7%; IQR, 013 for medical; and median, 10%; IQR 317 for oncology; P = 0.015). This was also reflected in a higher proportion of surgical patients never seen in an active upright position (44.1% compared to 27.1% medical and 22.0% oncology). Multivariate modeling showed no significant interaction between age and ward.
| All Ages, n = 132, Median Observations 29.5, Range 665* | Aged 65 Years, n = 61, Median Observations 30, Range 665 | Aged 65 Years, n = 67, Median Observations 27, Range 665 | |
|---|---|---|---|
| |||
| Location | |||
| Bedroom | 85.1 (13.3) | 84.6 (13.4) | 85.5 (12.9) |
| Bathroom | 3.0 (4.0) | 2.6 (3.9) | 3.4 (4.1) |
| Hall | 2.9 (4.6) | 3.4 (5.4) | 2.7 (4.0) |
| Lounge | 0.3 (1.9) | 0 | 0.6 (2.7) |
| Off ward/other | 8.6 (11.6) | 9.3 (11.4) | 7.8 (11.1) |
| Physical activity | |||
| Lie in bed | 57.4 (30.0) | 59.4 (29.4) | 55.5 (31.6) |
| Sit on bed | 21.0 (23.2) | 16.9 (19.9) | 24.7 (25.7) |
| Sit on chair | 12.6 (22.9) | 14.0 (25.6) | 11.9 (20.9) |
| Stand/walk/wheel | 9.0 (9.3) | 9.6 (9.6) | 8.0 (8.5) |
| Medical, n = 48, Median Observations 30, Range 759 | Oncology, n = 50, Median Observations 25, Range 652 | Surgical, n = 34, Median Observations 31, Range 1765 | |
|---|---|---|---|
| Location | |||
| Bedroom | 89.1 (11.4) | 81.3 (13.6) | 85.3 (14.1) |
| Bathroom | 2.8 (4.1) | 3.1 (3.8) | 3.1 (4.2) |
| Hall | 1.5 (2.5) | 5.3 (6.1) | 1.5 (2.7) |
| Lounge | 0.5 (2.0) | 0.4 (2.5) | 0 |
| Off ward/other | 6.2 (10.2) | 10.0 (11.9) | 10.1 (12.6) |
| Physical activity | |||
| Lie in bed | 53.3 (31.4) | 56.1 (30.2) | 65.1 (27.0) |
| Sit on bed | 30.3 (29.5) | 13.4 (16.1) | 19.0 (17.0) |
| Sit on chair | 8.2 (14.7) | 19.1 (29.1) | 9.3 (20.4) |
| Stand/walk/wheel | 8.2 (8.4) | 11.4 (9.7) | 6.5 (9.4) |
DISCUSSION
This observational cross‐sectional study extends previous observations of hospital inpatients to include a wider variety of patient types and ages. Observing 132 patients on medical, surgical, and oncology wards for up to 16 hours of weekday time, we found that patients spent only 9% in active upright postures, with significantly lower mobility on the surgical ward but no significant differences between older and younger patients.
Previous studies in older general medical patients using behavioral mapping[13] or accelerometers[2, 3] have shown 71% to 83% of time spent in bed, and 4% spent standing or walking, similar to our findings, although methodological differences between studies (eg, patient selection and time windows) caution against direct comparison. We identified different levels of physical activity on the surgical, medical, and oncology wards. This may reflect differences in patient case‐mix, ward environment, and/or ward culture. The medical and oncology wards each have a patient lounge, providing a potential walking destination, although only a small amount of patients' time was observed in these areas, suggesting that they may not fulfil their purpose. The oncology ward has a well developed wellness focus. The oncology and medical wards were actively involved in a quality‐improvement intervention to improve early patient mobility at the time of the audit,[15] whereas the surgical ward was at the precommencement (information gathering) stage. The data collected within this audit have formed part of the feedback cycle for staff involved in the improvement intervention. Repeat measurement will be undertaken on the surgical ward to help evaluate the impact of the intervention, and serial measurement will be undertaken in future participating wards to investigate the responsiveness of this measurement method.
Although the literature has focused on poor mobility in hospitalized elders, we did not find any better mobility in younger patients, suggesting that barriers to mobility are not confined to the elderly. Whereas individualized mobility assessment and support may be more important in the elderly,[16] addressing cultural and environmental issues such as promoting accountability for early ambulation, providing patients and families with permission and encouragement to ambulate, and ensuring accessible walking destinations may benefit patients of all ages.
Behavioral mapping has strengths and weaknesses compared to other methods such as accelerometry or patient/nurse report. Observations are conducted by an independent observer not involved in care and include all ward inpatients, providing a generalizable sample, as the observation protocol does not pose a participation burden for patient or ward staff. However, the cross‐sectional nature may oversample longer‐stay patients, the intermittent observation protocol tends to overestimate time spent upright,[14] the labor‐intensive nature of observations means choosing a limited time window (in our case 10001800), and the minimum time and observation frequency to generate reliable data remain uncertain. Further studies examining reliability, validity, and responsiveness would support the utility of this method for quality improvement.
In summary, this study shows that mobility is limited in older and younger adult inpatients across a range of inpatient wards, and that physical activity practices vary among wards. Interventions to enhance hospital mobility should include patients of all ages, and need to be tailored to local mobility practices, barriers, and enablers.
Acknowledgements
The authors thank the staff of wards 6AS, 9BN, and 7BW for participating in this project.
Disclosure: Nothing to report.
Low mobility is common in hospitalized older patients, and an independent predictor of poor functional outcomes.[1, 2, 3, 4] Few studies have included younger patients, but care models that support early mobility may reduce functional decline, enhance recovery, and reduce length of stay in older and mixed‐age populations.[5, 6] Barriers to mobility are complex and include patient symptoms and tethers, health provider behavior, team communication, and leadership, device availability, and environmental factors.[7, 8, 9, 10, 11] These contextual factors may differ even within a hospital between patient groups and ward settings. Simple measures to quantify mobility patterns would help address these barriers by providing opportunities for audit and feedback. Although accelerometry is the gold standard method for research, it requires equipment, analysis skills, and patient consent, which limits application in clinical practice. Behavioral mapping is a systematic method of observation developed in stroke patients, which is simple, objective, and requires no direct patient or staff participation,[12] and physical activity levels estimated from behavioral mapping are similar to those identified by accelerometry.[3, 13, 14] In the context of a phased quality‐improvement project aiming to reduce functional decline,[15] we undertook a cross‐sectional audit of mobility on 3 different wards using behavioral mapping, and examined differences among wards and between older (aged 65 years or more) and younger patients.
METHODS
This prospective observational study used cross‐sectional sampling from a 26‐bed general medical ward, a 30‐bed oncology ward, and a 24‐bed vascular surgical ward in a 900‐bed tertiary teaching hospital in Brisbane, Australia. Sampling was undertaken during 4 observation periods (2 mornings [10001400] and 2 afternoons [1400‐1800]) within 10 days in May 2013. All patients on each ward for each period were observed unless they were receiving end‐of‐life care. Structured observations were undertaken using behavioral mapping protocols similar to those previously described in stroke and general medical patients,[12, 13] with each patient room visited in the same sequence. Participants in each room were observed for a 2‐minute period (up to 4 participants could be observed concurrently in shared rooms) before moving to the next room, and the sequence was repeated in the same order for the whole 4‐hour period, with a single 15‐minute break. Depending on ward size and layout, this provided 12 to 17 observations per participant for each 4‐hour period (each individual observed every 1218 minutes). Observations were undertaken by 4 trained physiotherapy student observers using a predetermined set of mutually exclusive levels (lying in bed, sitting in or on the bed, sitting on a chair, standing, actively wheeling, or walking). The study was approved by the Royal Brisbane and Women's Hospital Human Research Ethics Committee as part of a quality‐improvement activity, and individual consent was not required. No clinical data except age and gender were collected for participants. The nurse unit manager for each ward was introduced to the observers and aware that observations were being conducted.
Patients who were observed for less than one‐half of an observation period were excluded so that all participants contributed at least 2 hours of observational data, up to a maximum of 16 hours. The number of valid observations for each participant (excluding time off ward or behind curtains if the level was not apparent) was calculated and used to derive the proportion of valid observations spent at each level for each participant. The proportion of observations at each level was summarized across all participants using frequency distributions and summary statistics. For ease of presentation, mean percentage of observed time in each activity was presented. However, as data were not normally distributed, statistical comparisons were undertaken using the Kruskal‐Wallis test, comparing the distribution of time spent upright (standing, walking, or actively wheeling) between groups (age group and ward). Interaction between age and ward effects was sought using generalized linear modeling.
RESULTS
Valid observations (at least 2 hours in 1 or more observation period) were available for 132 patients (48 medical, 50 oncology, and 34 surgery). Of these, 67 (51 %) were aged 65 years (54% medical, 44% oncology, 56% surgery) and 62 (47%) were male. There were a total of 3891 observations of location (median, 30 per patient; range, 965). Participants were observed in the bedded area 85.1% of observations, with 3.1% in the bathroom, 3.2% in the hallway or patient lounge, and 8.6% off ward. Allowing for time off ward and behind curtains, when observers could not be sure of their activity level, 3272 valid observations were available for physical activity.
More than half of the observed time (mean 57.4%) was spent lying in bed, 33.6% sitting on the bed or chair, and 9.0% standing, walking, or wheeling. Across all observation periods, 39/132 (29.5%) participants were never observed to be standing, walking or wheeling, and 7.6% were in bed at all observations. Comparing older and younger patients (Table 1), there was no difference in the time spent in active upright postures (median, 6.1% in older vs 7.4% in younger; P = 0.30). Table 2 summarizes descriptive data for the different wards. In the medical and surgical wards, 84% of the time was spend in or on the bed, and only 16% of the time was spent sitting in a chair or in active upright postures. Surgical patients, in particular, spent two‐thirds of observation time lying flat in bed, whereas medical patients spent more time sitting up on the bed. On statistical testing, time spent standing/walking/wheeling was significantly lower on the surgical ward (median, 4%; interquartile range [IQR], 010 for surgery; median, 7%; IQR, 013 for medical; and median, 10%; IQR 317 for oncology; P = 0.015). This was also reflected in a higher proportion of surgical patients never seen in an active upright position (44.1% compared to 27.1% medical and 22.0% oncology). Multivariate modeling showed no significant interaction between age and ward.
| All Ages, n = 132, Median Observations 29.5, Range 665* | Aged 65 Years, n = 61, Median Observations 30, Range 665 | Aged 65 Years, n = 67, Median Observations 27, Range 665 | |
|---|---|---|---|
| |||
| Location | |||
| Bedroom | 85.1 (13.3) | 84.6 (13.4) | 85.5 (12.9) |
| Bathroom | 3.0 (4.0) | 2.6 (3.9) | 3.4 (4.1) |
| Hall | 2.9 (4.6) | 3.4 (5.4) | 2.7 (4.0) |
| Lounge | 0.3 (1.9) | 0 | 0.6 (2.7) |
| Off ward/other | 8.6 (11.6) | 9.3 (11.4) | 7.8 (11.1) |
| Physical activity | |||
| Lie in bed | 57.4 (30.0) | 59.4 (29.4) | 55.5 (31.6) |
| Sit on bed | 21.0 (23.2) | 16.9 (19.9) | 24.7 (25.7) |
| Sit on chair | 12.6 (22.9) | 14.0 (25.6) | 11.9 (20.9) |
| Stand/walk/wheel | 9.0 (9.3) | 9.6 (9.6) | 8.0 (8.5) |
| Medical, n = 48, Median Observations 30, Range 759 | Oncology, n = 50, Median Observations 25, Range 652 | Surgical, n = 34, Median Observations 31, Range 1765 | |
|---|---|---|---|
| Location | |||
| Bedroom | 89.1 (11.4) | 81.3 (13.6) | 85.3 (14.1) |
| Bathroom | 2.8 (4.1) | 3.1 (3.8) | 3.1 (4.2) |
| Hall | 1.5 (2.5) | 5.3 (6.1) | 1.5 (2.7) |
| Lounge | 0.5 (2.0) | 0.4 (2.5) | 0 |
| Off ward/other | 6.2 (10.2) | 10.0 (11.9) | 10.1 (12.6) |
| Physical activity | |||
| Lie in bed | 53.3 (31.4) | 56.1 (30.2) | 65.1 (27.0) |
| Sit on bed | 30.3 (29.5) | 13.4 (16.1) | 19.0 (17.0) |
| Sit on chair | 8.2 (14.7) | 19.1 (29.1) | 9.3 (20.4) |
| Stand/walk/wheel | 8.2 (8.4) | 11.4 (9.7) | 6.5 (9.4) |
DISCUSSION
This observational cross‐sectional study extends previous observations of hospital inpatients to include a wider variety of patient types and ages. Observing 132 patients on medical, surgical, and oncology wards for up to 16 hours of weekday time, we found that patients spent only 9% in active upright postures, with significantly lower mobility on the surgical ward but no significant differences between older and younger patients.
Previous studies in older general medical patients using behavioral mapping[13] or accelerometers[2, 3] have shown 71% to 83% of time spent in bed, and 4% spent standing or walking, similar to our findings, although methodological differences between studies (eg, patient selection and time windows) caution against direct comparison. We identified different levels of physical activity on the surgical, medical, and oncology wards. This may reflect differences in patient case‐mix, ward environment, and/or ward culture. The medical and oncology wards each have a patient lounge, providing a potential walking destination, although only a small amount of patients' time was observed in these areas, suggesting that they may not fulfil their purpose. The oncology ward has a well developed wellness focus. The oncology and medical wards were actively involved in a quality‐improvement intervention to improve early patient mobility at the time of the audit,[15] whereas the surgical ward was at the precommencement (information gathering) stage. The data collected within this audit have formed part of the feedback cycle for staff involved in the improvement intervention. Repeat measurement will be undertaken on the surgical ward to help evaluate the impact of the intervention, and serial measurement will be undertaken in future participating wards to investigate the responsiveness of this measurement method.
Although the literature has focused on poor mobility in hospitalized elders, we did not find any better mobility in younger patients, suggesting that barriers to mobility are not confined to the elderly. Whereas individualized mobility assessment and support may be more important in the elderly,[16] addressing cultural and environmental issues such as promoting accountability for early ambulation, providing patients and families with permission and encouragement to ambulate, and ensuring accessible walking destinations may benefit patients of all ages.
Behavioral mapping has strengths and weaknesses compared to other methods such as accelerometry or patient/nurse report. Observations are conducted by an independent observer not involved in care and include all ward inpatients, providing a generalizable sample, as the observation protocol does not pose a participation burden for patient or ward staff. However, the cross‐sectional nature may oversample longer‐stay patients, the intermittent observation protocol tends to overestimate time spent upright,[14] the labor‐intensive nature of observations means choosing a limited time window (in our case 10001800), and the minimum time and observation frequency to generate reliable data remain uncertain. Further studies examining reliability, validity, and responsiveness would support the utility of this method for quality improvement.
In summary, this study shows that mobility is limited in older and younger adult inpatients across a range of inpatient wards, and that physical activity practices vary among wards. Interventions to enhance hospital mobility should include patients of all ages, and need to be tailored to local mobility practices, barriers, and enablers.
Acknowledgements
The authors thank the staff of wards 6AS, 9BN, and 7BW for participating in this project.
Disclosure: Nothing to report.
- , , . Prevalence and outcomes of low mobility in hospitalized older patients. J Am Geriatr Soc. 2004;52(8):1263–1270.
- , , , . The underrecognized epidemic of low mobility during hospitalization of older adults. J Am Geriatr Soc. 2009;57:1660–1665.
- , , , et al. Twenty‐four‐hour mobility during acute hospitalization in older medical patients. J Gerontol A Biol Sci Med Sci. 2013;68(3):331–337.
- , , , , , . Low mobility during hospitalization and functional decline in older adults. J Am Geriatr Soc. 2011;59(2):266–273.
- , , . Exercising body and mind: an integrated approach to functional independence. J Am Geriatr Soc. 2008;56:630–635.
- , , , , . Early mobilization of patients hospitalized with community‐acquired pneumonia. Chest. 2003;124(124):883–889.
- , , . Nursing staff perceptions of physical function in hospitalized older adults. App Nurs Res. 2011;24:215–222.
- , , , , . Barriers to mobility during hospitalization from the perspectives of older patients and their nurses and physicians. J Hosp Med. 2007;2:305–313.
- , . How nurses decide to ambulate hospitalized older adults: development of a conceptual model. Gerontologist. 2011;51(6):786–797.
- , , , . Barriers to early mobility of hospitalized general medicine patients. Survey development and validation. Am J Phys Med Rehabil. 2015;94:304–312.
- , . Attitudes and expectations regarding exercise in the hospital of hospitalized older adults: a qualitative study. J Am Geriatr Soc. 2012;60:713–718.
- , , , . Inactive and alone. Physical activity within the first 14 days of acute stroke unit care. Stroke. 2004;35:1005–1009.
- , , . Activity level of hospital medical inpatients: an observational study. Arch Gerontol Geriatr. 2012;55:417–421.
- , , , . Measuring activity levels at an acute stroke ward: comparing observations to a device. Biomed Res Int. 2013;2013:460482.
- , , . Eat walk engage: an interdisciplinary collaborative model to improve care of hospitalized elders. Am J Med Qual. 2015;30(1):5–13.
- , , . Hospitalization‐associated disability. “She was probably able to ambulate, but I'm not sure”. JAMA. 2011;306(16):1782–1793.
- , , . Prevalence and outcomes of low mobility in hospitalized older patients. J Am Geriatr Soc. 2004;52(8):1263–1270.
- , , , . The underrecognized epidemic of low mobility during hospitalization of older adults. J Am Geriatr Soc. 2009;57:1660–1665.
- , , , et al. Twenty‐four‐hour mobility during acute hospitalization in older medical patients. J Gerontol A Biol Sci Med Sci. 2013;68(3):331–337.
- , , , , , . Low mobility during hospitalization and functional decline in older adults. J Am Geriatr Soc. 2011;59(2):266–273.
- , , . Exercising body and mind: an integrated approach to functional independence. J Am Geriatr Soc. 2008;56:630–635.
- , , , , . Early mobilization of patients hospitalized with community‐acquired pneumonia. Chest. 2003;124(124):883–889.
- , , . Nursing staff perceptions of physical function in hospitalized older adults. App Nurs Res. 2011;24:215–222.
- , , , , . Barriers to mobility during hospitalization from the perspectives of older patients and their nurses and physicians. J Hosp Med. 2007;2:305–313.
- , . How nurses decide to ambulate hospitalized older adults: development of a conceptual model. Gerontologist. 2011;51(6):786–797.
- , , , . Barriers to early mobility of hospitalized general medicine patients. Survey development and validation. Am J Phys Med Rehabil. 2015;94:304–312.
- , . Attitudes and expectations regarding exercise in the hospital of hospitalized older adults: a qualitative study. J Am Geriatr Soc. 2012;60:713–718.
- , , , . Inactive and alone. Physical activity within the first 14 days of acute stroke unit care. Stroke. 2004;35:1005–1009.
- , , . Activity level of hospital medical inpatients: an observational study. Arch Gerontol Geriatr. 2012;55:417–421.
- , , , . Measuring activity levels at an acute stroke ward: comparing observations to a device. Biomed Res Int. 2013;2013:460482.
- , , . Eat walk engage: an interdisciplinary collaborative model to improve care of hospitalized elders. Am J Med Qual. 2015;30(1):5–13.
- , , . Hospitalization‐associated disability. “She was probably able to ambulate, but I'm not sure”. JAMA. 2011;306(16):1782–1793.
TUBB8 mutations cause some female infertility
Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.
The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.
Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.
The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.
The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).
Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.
“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.
The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
The experimental data provided by Feng et al. are unusual in their breadth. Introducing the TUBB8 mutations they identified into HeLa cells, yeast cells, mouse oocytes, and human oocytes disrupted the microtubule networks in all. Depending on the mutation and the specific cell type, these defects ranged from flawed heterodimer assembly to complete obliteration of the microtubule network.
These findings will likely lead to improved diagnoses at fertility clinics. They also offer a potential foundation for discovering other genetic causes of primary female infertility.
Dr. Jurrien Dean is at the Laboratory of Cellular and Developmental Biology at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. He reported having no relevant financial disclosures. These comments are adapted from an editorial by Dr. Dean (N Engl J Med. 2016 Jan 20. doi:10.1056/NEJMe1515512.).
The experimental data provided by Feng et al. are unusual in their breadth. Introducing the TUBB8 mutations they identified into HeLa cells, yeast cells, mouse oocytes, and human oocytes disrupted the microtubule networks in all. Depending on the mutation and the specific cell type, these defects ranged from flawed heterodimer assembly to complete obliteration of the microtubule network.
These findings will likely lead to improved diagnoses at fertility clinics. They also offer a potential foundation for discovering other genetic causes of primary female infertility.
Dr. Jurrien Dean is at the Laboratory of Cellular and Developmental Biology at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. He reported having no relevant financial disclosures. These comments are adapted from an editorial by Dr. Dean (N Engl J Med. 2016 Jan 20. doi:10.1056/NEJMe1515512.).
The experimental data provided by Feng et al. are unusual in their breadth. Introducing the TUBB8 mutations they identified into HeLa cells, yeast cells, mouse oocytes, and human oocytes disrupted the microtubule networks in all. Depending on the mutation and the specific cell type, these defects ranged from flawed heterodimer assembly to complete obliteration of the microtubule network.
These findings will likely lead to improved diagnoses at fertility clinics. They also offer a potential foundation for discovering other genetic causes of primary female infertility.
Dr. Jurrien Dean is at the Laboratory of Cellular and Developmental Biology at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. He reported having no relevant financial disclosures. These comments are adapted from an editorial by Dr. Dean (N Engl J Med. 2016 Jan 20. doi:10.1056/NEJMe1515512.).
Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.
The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.
Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.
The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.
The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).
Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.
“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.
The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
Certain cases of female infertility appear to be caused by mutations in the TUBB8 gene that impair microtubule behavior and meiotic spindle assembly, thus preventing oocyte maturation, according to a report published online Jan. 20 in the New England Journal of Medicine.
The findings from a series of genetic analyses “provide the basis for developing diagnostic tools” to identify women who carry these mutations, and also point the way to as-yet undiscovered genetic mutations that also contribute to the arrest of oocyte maturation, wrote Ruizhi Feng, Ph.D., of State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, and his associates.
Immature oocytes are arrested at a phase of development before complete meiosis occurs. Among women seeking in vitro fertilization “it is common for some oocytes to remain immature after ovarian stimulation and administration of human chorionic gonadotropin, but complete arrest of oocyte maturation has been reported in only a few women, and nothing is known about the genetic cause of this phenotype,” they noted.
The investigators identified a four-generation family affected with a rare pattern of inheritance of female infertility, which was found to stem from complete oocyte maturation arrest. They sequenced the exomes of three affected and two unaffected women in the family. All the affected women, but none of the unaffected women, carried a mutation in the TUBB8 gene that encodes for a tubulin isotope. The researchers then found six other TUBB8 mutations (all paternally transmitted) in seven women from four other families with similar oocyte maturation arrest, as well as de novo mutations in two women from two additional families. All of the oocytes assessed either had abnormal spindles or no detectable spindles.
The investigators hypothesized that TUBB8 influences the self-organization of microtubules, and thus meiotic spindle assembly and chromosome orientation, in oocytes. Further analyses confirmed this and showed that the mutations affected tubulin heterodimer folding and assembly in vitro, caused “a spectrum of striking microtubule phenotypes” in cultured HeLa cells, and markedly impaired microtubule dynamics in in-vivo yeast colonies (N Engl J Med 2016;374:223-32. doi:10.1056/NEJMoa1510791).
Finally, to establish a causal relationship between the TUBB8 mutations and infertility, the investigators introduced them into mouse and human oocytes. The TUBB8 mutations caused maturation defects “that precisely mimic the infertility phenotype,” while nonmutated TUBB8 did not, they reported.
“We conclude from these observations that mutations in TUBB8 cause oocyte maturation arrest and that TUBB8 has a key role in meiotic spindle assembly and maturation in human oocytes,” Dr. Feng and his associates wrote.
The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Mutations in the TUBB8 gene cause some female infertility by impairing microtubule behavior, meiotic spindle assembly, and oocyte maturation.
Major finding: Researchers identified seven mutations in the gene TUBB8 that were responsible for oocyte meiosis arrest in seven of 24 families.
Data source: A series of genetic analyses, including assessment of 24 Chinese families with infertility due to arrest of oocyte maturation.
Disclosures: The National Basic Research Program of China, the Shanghai Key Scientific Research Program, the National Natural Science Foundation of China, the 111 Project, and the U.S. National Institutes of Health supported the study. Dr. Feng and his associates reported having no conflicts of interest.
Biomarker may ID high-risk colon cancers
A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.
Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.
The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.
Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).
The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.
To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).
This survival benefit was independent of many known risk factors, including tumor grade, they noted.
These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.
This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
These study findings give clinicians the opportunity to move beyond the existing inadequate method of selecting patients for adjuvant chemotherapy. Although this was not a perfect or definitive study, since it was retrospective and the number of patients with CDX2-negative colon cancers was relatively small, it nevertheless entailed numerous rigorous data analyses.
|
Dr. C. Richard Boland |
Moreover, the results raise the important question of what mechanism might be silencing CDX2 in this subset of aggressive cancers. The answer could lead to the discovery of new approaches to treating the underlying problem.
C. Richard Boland, M.D., and Ajay Goel, Ph.D., are at the Center for Gastrointestinal Research and the Center for Epigenetics, Cancer Prevention, and Genomics at Baylor Research Institute, and at the Baylor Charles A. Sammons Cancer Center, all in Dallas. They reported having no relevant financial disclosures. Dr. Boland and Dr. Goel made these remarks in an editorial accompanying Dr. Dalerba’s report (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMe1514353).
These study findings give clinicians the opportunity to move beyond the existing inadequate method of selecting patients for adjuvant chemotherapy. Although this was not a perfect or definitive study, since it was retrospective and the number of patients with CDX2-negative colon cancers was relatively small, it nevertheless entailed numerous rigorous data analyses.
|
|
Dr. C. Richard Boland |
Moreover, the results raise the important question of what mechanism might be silencing CDX2 in this subset of aggressive cancers. The answer could lead to the discovery of new approaches to treating the underlying problem.
C. Richard Boland, M.D., and Ajay Goel, Ph.D., are at the Center for Gastrointestinal Research and the Center for Epigenetics, Cancer Prevention, and Genomics at Baylor Research Institute, and at the Baylor Charles A. Sammons Cancer Center, all in Dallas. They reported having no relevant financial disclosures. Dr. Boland and Dr. Goel made these remarks in an editorial accompanying Dr. Dalerba’s report (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMe1514353).
These study findings give clinicians the opportunity to move beyond the existing inadequate method of selecting patients for adjuvant chemotherapy. Although this was not a perfect or definitive study, since it was retrospective and the number of patients with CDX2-negative colon cancers was relatively small, it nevertheless entailed numerous rigorous data analyses.
|
|
Dr. C. Richard Boland |
Moreover, the results raise the important question of what mechanism might be silencing CDX2 in this subset of aggressive cancers. The answer could lead to the discovery of new approaches to treating the underlying problem.
C. Richard Boland, M.D., and Ajay Goel, Ph.D., are at the Center for Gastrointestinal Research and the Center for Epigenetics, Cancer Prevention, and Genomics at Baylor Research Institute, and at the Baylor Charles A. Sammons Cancer Center, all in Dallas. They reported having no relevant financial disclosures. Dr. Boland and Dr. Goel made these remarks in an editorial accompanying Dr. Dalerba’s report (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMe1514353).
A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.
Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.
The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.
Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).
The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.
To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).
This survival benefit was independent of many known risk factors, including tumor grade, they noted.
These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.
This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify the approximately 20% of stage II and 50% of stage III colon cancers that are at high risk of recurrence and would benefit from adjuvant chemotherapy, according to a report published online Jan. 21 in the New England Journal of Medicine.
Distinguishing the high-risk tumors from those unlikely to recur or progress would allow some patients to opt for adjuvant chemotherapy that has been shown to significantly raise the rates of overall and disease-free survival. At present, almost all patients with stage II colon cancer are treated using surgery alone, said Dr. Piero Dalerba of the Herbert Irving Comprehensive Cancer Center and the department of pathology and cell biology at Columbia University, New York, and his associates.
The investigators used a bioinformatics approach to search for biomarkers that would identify the most aggressive colon cancers: undifferentiated tumors characterized by immature, stem-like colonic epithelial cells and depleted of more mature cells. They focused on biomarkers for which clinical diagnostic tests are already available, to facilitate use in real-world clinical practice. Their search through 2,329 colon gene-expression array experiments found that when tumors do not express one particular protein, homeobox transcription factor CDX2, “a master regulator of intestinal development and oncogenesis” that is highly specifically expressed in intestinal epithelium, those tumors tend to have aggressive features such as advanced stage, vascular invasion, and BRAF mutation.
Survival outcomes were then compared in a discovery data set of 466 patients. The 5-year disease-free survival rate was significantly lower, at 41%, among the 32 patients who had CDX2-negative tumors than the 74% survival rate among the 434 patients with CDX2-positive tumors. The hazard ratio for disease recurrence among patients with CDX2-negative vs. CDX2-positive tumors was 2.73, Dr. Dalerba and his associates said (N Engl J Med. 2016 Jan 21. doi:10.1056/NEJMoa1506597).
The investigators confirmed these findings in a separate validation data set of 366 patients, of whom 48 had CDX2-negative and 318 had CDX2-positive tumors. Five-year disease-free survival (48% vs. 71%), overall survival (33% vs. 59%), and disease-specific survival (45% vs. 72%) were significantly lower with CDX2-negative tumors, and the HR for disease recurrence was 2.42.
To determine whether adjuvant chemotherapy would improve survival outcomes in patients with CDX2-negative tumors, the researchers assessed outcomes in an expanded dataset of 669 patients with stage II and 1,228 patients with stage III colon cancer. They confirmed that among patients with stage II CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (91%) than did those who didn’t receive adjuvant chemotherapy (56%). Similarly, among patients with stage III CDX2-negative tumors, those who received adjuvant chemotherapy had a higher rate of disease-free survival (74%) than those who did not receive adjuvant chemotherapy (37%).
This survival benefit was independent of many known risk factors, including tumor grade, they noted.
These results must be replicated in future prospective studies, because this study’s design was retrospective and exploratory, Dr. Dalerba and his associates added.
This work was supported by the National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: A biomarker for which a screening test is already available – lack of CDX2 expression – appears to identify which stage II and III colon cancers are high-risk and would benefit from adjuvant chemotherapy.
Major finding: Five-year disease-free survival rate was significantly lower (41%) in patients who had CDX2-negative tumors than in patients with CDX2-positive tumors (74%).
Data source: A series of analyses using data mining to identify (in a database of 466 patients) and validate (in databases of 366 and 1,897 patients) a biomarker for early colon cancers at high risk for recurrence/metastasis.
Disclosures: The National Comprehensive Cancer Network, the National Institutes of Health, Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the U.S. Department of Defense, the Bladder Cancer Advocacy Network, and BD Biosciences supported the work. Dr. Dalerba reported ties to Quanticel Pharmaceuticals and Oncomed Pharmaceuticals, and his associates reported ties to numerous industry sources.
MRI findings beyond sacroiliitis not necessary for classifying nonradiographic axial SpA
Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.
The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).
The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”
Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”
Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.
The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.
In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).
The working panel and commentary authors declared having no competing interests.
Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.
The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).
The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”
Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”
Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.
The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.
In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).
The working panel and commentary authors declared having no competing interests.
Current recommendations for identifying sacroiliitis on MRI to classify patients with nonradiographic axial spondyloarthritis should still depend on the presence of subchondral bone marrow edema, but additional evidence of structural lesions can be taken into account to define the presence of inflammatory lesions, according to a consensus review by experts from the Assessment in SpondyloArthritis International Society MRI working group.
The additional information provided by structural lesions, such as erosions, detected via MRI of the sacroiliac (SI) joint or spine is not necessary for the definition, but “may enhance confidence in the classification of axial SpA [spondyloarthritis],” said the panel of 16 rheumatologists, 4 radiologists, and 1 research fellow, who presented their summary and draft proposal at the January 2014 annual assembly of the Assessment in SpondyloArthritis International Society (ASAS), where members unanimously approved it (Ann Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208642).
The group’s goal was to examine whether new data published on axial SpA in the 5 years following the 2009 publication of the ASAS recommendations were “sufficient to merit a change in the MRI definition of a positive MRI and clarify any misunderstanding of the existing definition.”
Overall, the working group determined that the addition of “structural damage changes of the SI joints and the addition of features on MRI of the spine for classification purposes is not yet clear and this continues to be an important research agenda.”
Adding any single lesion or combination of lesions to the current classification criteria for nonradiographic axial spondyloarthritis (nr-axSpA) did not increase the sensitivity of the MRI definition without losing specificity in one cohort, whereas there was an unclear benefit to adding SI erosion to the definition in another cohort. The evaluation of these lesions on MRI depended on the use of T1 weighting and fat-suppression techniques, as well as the contextual interpretation of MRI, which currently add too much complexity to the definition of a positive SI joint MRI to be useful in achieving a “consensus for definitions for each MRI structural damage lesion and the setting of thresholds for any defined lesion or combination of lesions,” the working group wrote.
The panelists found that there was no consistent beneficial effect of adding features of SpA on spine MRI to the definition. Spine MRI added incremental sensitivity in other analyses, but also increased false-positive SpA diagnoses.
In a commentary reviewing the controversy and evidence for classifying diseases within the spectrum of axial SpA, Dr. Atul Deodhar of Oregon Health and Science University, Portland, and his colleagues noted that “there is no need to differentiate between a diagnosis of nr-axSpA and that of [ankylosing spondylitis] in clinical practice, since the only purpose for having these two labels is classification.” They said the need for formal distinction between nr-axSpA and ankylosing spondylitis may require some exceptions, such as when it is necessary “to specify an approved indication for TNFi [tumor necrosis factor inhibitor] therapy, when off-label use of biologics must be avoided ... and to clarify the presence of structural changes that are required for patients to receive coverage from their insurance carrier to use a TNFi” (Ann. Rheum Dis. 2016 Jan 14. doi: 10.1136/annrheumdis-2015-208852).
The working panel and commentary authors declared having no competing interests.
FROM ANNALS OF THE RHEUMATIC DISEASES
Experts say abandon aspirin for stroke prevention in atrial fib
SNOWMASS, COLO. – It’s time to eliminate the practice of prescribing aspirin for stroke prevention in patients with atrial fibrillation and a CHA2DS2-VASc score of 1, two eminent cardiologists agreed at the Annual Cardiovascular Conference at Snowmass.
“The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current U.S. guidelines. I don’t think aspirin should be in there and I don’t think it will be there in the next guidelines. The role of aspirin will fall away,” predicted Dr. Bernard J. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
“It’s not that aspirin is less effective than the oral anticoagulants, it’s that there’s no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation,” he declared.
Dr. N.A. Mark Estes III agreed the aspirin evidence is seriously flawed.
“The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly,” according to Dr. Estes, a past president of the Heart Rhythm Society who is professor of medicine and director of the New England Cardiac Arrhythmia Center at Tufts University, Boston.
The sole positive clinical trial of aspirin versus placebo, the 25-year-old Stroke Prevention in Atrial Fibrillation (SPAF) study (Circulation. 1991 Aug;84[2]:527-39), found an unrealistically high stroke protection benefit for aspirin, a result made implausible by multiple other randomized trials showing no benefit, the cardiologists agreed.
“In our current guidelines for atrial fibrillation (Circulation. 2014 Dec 2;130[23]:2071-104), aspirin can be considered as a Class IIb level of evidence C recommendation in patients with a CHA2DS2-VASc of 1. But I would just take it off of your clinical armamentarium because the best available data indicates that it doesn’t prevent strokes. I’m certainly not using it in my patients. Increasingly in my patients with a CHA2DS2-VASc of 1, I’m discussing the risks and benefits of a NOAC [novel oral anticoagulant],” Dr. Estes said.
Dr. Gersh was also critical of another common practice in stroke prevention in atrial fibrillation: concomitant use of aspirin with an oral anticoagulant.
“We use too much aspirin in patients on oral anticoagulation. Aspirin is perhaps the major cause of bleeding in patients on an oral anticoagulant. Other than in people with a drug-eluting stent, there’s no role at all for aspirin in stroke prevention,” he asserted.
He was coauthor of an analysis of 7,347 participants in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) who were on an oral anticoagulant. Fully 35% of them were also on aspirin. In a multivariate analysis, concomitant aspirin and oral anticoagulation was independently associated with a 53% increased risk of major bleeding and a 52% increase in hospitalization for bleeding, compared with atrial fibrillation patients on an oral anticoagulant alone (Circulation. 2013 Aug 13;128[7]:721-8).
Moreover, the widespread use of dual therapy in this real-world registry didn’t appear to be rational. Thirty-nine percent of those on aspirin plus an oral anticoagulant had no history of atherosclerotic disease, the presence of which would be an indication for considering aspirin. And 17% of dual therapy patients had an elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score of 5 or more, making dual therapy particularly risky.
This clinically important interaction between aspirin and oral anticoagulation was recently underscored in an analysis of rivaroxaban-treated patients in the ROCKET AF trial, Dr. Gersh observed. Long-term use of aspirin at entry into this pivotal randomized trial of rivaroxaban (Xarelto) versus warfarin in patients with atrial fibrillation proved to be an independent predictor of a 47% increase in the risk of gastrointestinal bleeding, compared with patients on rivaroxaban alone (J Am Coll Cardiol. 2015 Dec 1;66[21]:2271-81).
He added that there is no evidence that combining aspirin and oral anticoagulation enhances stroke prevention beyond the marked benefit achieved with oral anticoagulation alone.
Dr. Gersh reported serving on the leadership of the ORBIT-AF Registry, which was sponsored by Janssen Pharmaceuticals. Dr. Estes reported having no financial conflicts relevant to this discussion.
SNOWMASS, COLO. – It’s time to eliminate the practice of prescribing aspirin for stroke prevention in patients with atrial fibrillation and a CHA2DS2-VASc score of 1, two eminent cardiologists agreed at the Annual Cardiovascular Conference at Snowmass.
“The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current U.S. guidelines. I don’t think aspirin should be in there and I don’t think it will be there in the next guidelines. The role of aspirin will fall away,” predicted Dr. Bernard J. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
“It’s not that aspirin is less effective than the oral anticoagulants, it’s that there’s no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation,” he declared.
Dr. N.A. Mark Estes III agreed the aspirin evidence is seriously flawed.
“The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly,” according to Dr. Estes, a past president of the Heart Rhythm Society who is professor of medicine and director of the New England Cardiac Arrhythmia Center at Tufts University, Boston.
The sole positive clinical trial of aspirin versus placebo, the 25-year-old Stroke Prevention in Atrial Fibrillation (SPAF) study (Circulation. 1991 Aug;84[2]:527-39), found an unrealistically high stroke protection benefit for aspirin, a result made implausible by multiple other randomized trials showing no benefit, the cardiologists agreed.
“In our current guidelines for atrial fibrillation (Circulation. 2014 Dec 2;130[23]:2071-104), aspirin can be considered as a Class IIb level of evidence C recommendation in patients with a CHA2DS2-VASc of 1. But I would just take it off of your clinical armamentarium because the best available data indicates that it doesn’t prevent strokes. I’m certainly not using it in my patients. Increasingly in my patients with a CHA2DS2-VASc of 1, I’m discussing the risks and benefits of a NOAC [novel oral anticoagulant],” Dr. Estes said.
Dr. Gersh was also critical of another common practice in stroke prevention in atrial fibrillation: concomitant use of aspirin with an oral anticoagulant.
“We use too much aspirin in patients on oral anticoagulation. Aspirin is perhaps the major cause of bleeding in patients on an oral anticoagulant. Other than in people with a drug-eluting stent, there’s no role at all for aspirin in stroke prevention,” he asserted.
He was coauthor of an analysis of 7,347 participants in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) who were on an oral anticoagulant. Fully 35% of them were also on aspirin. In a multivariate analysis, concomitant aspirin and oral anticoagulation was independently associated with a 53% increased risk of major bleeding and a 52% increase in hospitalization for bleeding, compared with atrial fibrillation patients on an oral anticoagulant alone (Circulation. 2013 Aug 13;128[7]:721-8).
Moreover, the widespread use of dual therapy in this real-world registry didn’t appear to be rational. Thirty-nine percent of those on aspirin plus an oral anticoagulant had no history of atherosclerotic disease, the presence of which would be an indication for considering aspirin. And 17% of dual therapy patients had an elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score of 5 or more, making dual therapy particularly risky.
This clinically important interaction between aspirin and oral anticoagulation was recently underscored in an analysis of rivaroxaban-treated patients in the ROCKET AF trial, Dr. Gersh observed. Long-term use of aspirin at entry into this pivotal randomized trial of rivaroxaban (Xarelto) versus warfarin in patients with atrial fibrillation proved to be an independent predictor of a 47% increase in the risk of gastrointestinal bleeding, compared with patients on rivaroxaban alone (J Am Coll Cardiol. 2015 Dec 1;66[21]:2271-81).
He added that there is no evidence that combining aspirin and oral anticoagulation enhances stroke prevention beyond the marked benefit achieved with oral anticoagulation alone.
Dr. Gersh reported serving on the leadership of the ORBIT-AF Registry, which was sponsored by Janssen Pharmaceuticals. Dr. Estes reported having no financial conflicts relevant to this discussion.
SNOWMASS, COLO. – It’s time to eliminate the practice of prescribing aspirin for stroke prevention in patients with atrial fibrillation and a CHA2DS2-VASc score of 1, two eminent cardiologists agreed at the Annual Cardiovascular Conference at Snowmass.
“The European guidelines have done away with aspirin for stroke prevention in atrial fibrillation. It barely made it into our current U.S. guidelines. I don’t think aspirin should be in there and I don’t think it will be there in the next guidelines. The role of aspirin will fall away,” predicted Dr. Bernard J. Gersh, professor of medicine at the Mayo Clinic in Rochester, Minn.
“It’s not that aspirin is less effective than the oral anticoagulants, it’s that there’s no role for it. There are no good data to support aspirin in the prevention of stroke in atrial fibrillation,” he declared.
Dr. N.A. Mark Estes III agreed the aspirin evidence is seriously flawed.
“The use of aspirin has probably been misguided, based upon a single trial which showed a profound effect and was probably just an anomaly,” according to Dr. Estes, a past president of the Heart Rhythm Society who is professor of medicine and director of the New England Cardiac Arrhythmia Center at Tufts University, Boston.
The sole positive clinical trial of aspirin versus placebo, the 25-year-old Stroke Prevention in Atrial Fibrillation (SPAF) study (Circulation. 1991 Aug;84[2]:527-39), found an unrealistically high stroke protection benefit for aspirin, a result made implausible by multiple other randomized trials showing no benefit, the cardiologists agreed.
“In our current guidelines for atrial fibrillation (Circulation. 2014 Dec 2;130[23]:2071-104), aspirin can be considered as a Class IIb level of evidence C recommendation in patients with a CHA2DS2-VASc of 1. But I would just take it off of your clinical armamentarium because the best available data indicates that it doesn’t prevent strokes. I’m certainly not using it in my patients. Increasingly in my patients with a CHA2DS2-VASc of 1, I’m discussing the risks and benefits of a NOAC [novel oral anticoagulant],” Dr. Estes said.
Dr. Gersh was also critical of another common practice in stroke prevention in atrial fibrillation: concomitant use of aspirin with an oral anticoagulant.
“We use too much aspirin in patients on oral anticoagulation. Aspirin is perhaps the major cause of bleeding in patients on an oral anticoagulant. Other than in people with a drug-eluting stent, there’s no role at all for aspirin in stroke prevention,” he asserted.
He was coauthor of an analysis of 7,347 participants in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) who were on an oral anticoagulant. Fully 35% of them were also on aspirin. In a multivariate analysis, concomitant aspirin and oral anticoagulation was independently associated with a 53% increased risk of major bleeding and a 52% increase in hospitalization for bleeding, compared with atrial fibrillation patients on an oral anticoagulant alone (Circulation. 2013 Aug 13;128[7]:721-8).
Moreover, the widespread use of dual therapy in this real-world registry didn’t appear to be rational. Thirty-nine percent of those on aspirin plus an oral anticoagulant had no history of atherosclerotic disease, the presence of which would be an indication for considering aspirin. And 17% of dual therapy patients had an elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score of 5 or more, making dual therapy particularly risky.
This clinically important interaction between aspirin and oral anticoagulation was recently underscored in an analysis of rivaroxaban-treated patients in the ROCKET AF trial, Dr. Gersh observed. Long-term use of aspirin at entry into this pivotal randomized trial of rivaroxaban (Xarelto) versus warfarin in patients with atrial fibrillation proved to be an independent predictor of a 47% increase in the risk of gastrointestinal bleeding, compared with patients on rivaroxaban alone (J Am Coll Cardiol. 2015 Dec 1;66[21]:2271-81).
He added that there is no evidence that combining aspirin and oral anticoagulation enhances stroke prevention beyond the marked benefit achieved with oral anticoagulation alone.
Dr. Gersh reported serving on the leadership of the ORBIT-AF Registry, which was sponsored by Janssen Pharmaceuticals. Dr. Estes reported having no financial conflicts relevant to this discussion.
EXPERT ANALYSIS FROM THE CARDIOVASCULAR CONFERENCE AT SNOWMASS
Understanding stillbirth
When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.
In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.
In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.
For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.
When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.
In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.
In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.
For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.
When a couple learns that “they are pregnant,” it is often one of the most joyous moments in their lives. However, despite the modern prenatal care available to women in the United States, pregnancy loss remains a real concern. Miscarriage is estimated to occur in 15%-20% of pregnancies; recurrent pregnancy loss in about 1%-2% of pregnancies; and stillbirth in as many as 1% of pregnancies. The causes of pregnancy loss can range from those we can diagnose, such as genetic factors, anatomic complications, and thrombophilia, to those that elude us completely.
In December 2015, investigators from Karolinska Institutet in Stockholm published a study indicating that women who gained weight between their first and second pregnancies, but who were a healthy weight prior to their first pregnancy, had an increased risk of experiencing a stillbirth (30%-50%), or having an infant who died within the first year (27%-60%) (Lancet 2015. doi: 10.1016/S0140-6736(15)00990-3). We have devoted a number of Master Class columns to the link between obesity and pregnancy complications, and this study further reinforces the influence of a healthy weight on pregnancy outcomes.
In addition to lifestyle modifications, evidence has suggested that low-molecular-weight heparin, aspirin, or vitamin supplements, in combination with appropriate surveillance and management, may reduce risk of pregnancy loss. However, more work is needed to fully understand why fetal death occurs if we are to better equip ourselves, and our patients, with all the information necessary to prevent loss from happening.
For this reason, we have invited Dr. Uma M. Reddy of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, to address one of the most devastating types of pregnancy losses: stillbirth. As a program scientist for large research studies, such as the Stillbirth Collaborative Research Network, Dr. Reddy’s unique perspective will add greatly to our understanding of pregnancy loss.
Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece reported having no relevant financial disclosures. He is the medical editor of this column.
Research adds insight on stillbirth risk factors
Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).
Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.
What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.
Risks and causes
Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.
Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.
Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.
As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).
The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).
A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).
In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).
A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).
Work-up and prevention
Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.
Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.
In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.
Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).
When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.
Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.
In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).
A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.
Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.
In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.
For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).
Current research
One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).
Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).
In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.
Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.
Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).
The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.
Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.
Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).
Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.
What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.
Risks and causes
Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.
Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.
Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.
As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).
The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).
A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).
In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).
A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).
Work-up and prevention
Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.
Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.
In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.
Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).
When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.
Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.
In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).
A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.
Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.
In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.
For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).
Current research
One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).
Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).
In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.
Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.
Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).
The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.
Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.
Stillbirth is a major public health problem, occurring in approximately 1 of every 160 pregnancies in the United States. The rate has remained stagnant since 2006. Prior to that time, from 1990 to 2006, the rate declined somewhat, but only half as much as the decline in infant mortality during this time period. Racial disparities also have persisted, with non-Hispanic black women having more than a twofold increase in risk (Natl Vital Stat Rep. 2012;60:1-22).
Research conducted by the Stillbirth Collaborative Research Network (SCRN) and others has provided us with insight on risk factors and on probable and possible causes of death among stillbirths, which are defined as fetal deaths at 20 or more weeks’ gestation. We know from SCRN data, for instance, that black women are more likely to have stillbirths associated with obstetric complications and infections than white and Hispanic women. However, we still cannot explain a substantial proportion of stillbirths, despite a complete evaluation, or predict who will have a stillbirth.
What we can do as obstetricians is be aware that stillbirth is one of the most common adverse pregnancy outcomes in the United States and counsel women regarding risk factors that are modifiable. Moreover, when stillbirth happens, a complete postmortem evaluation that includes autopsy, placental pathology, karyotype or microarray analysis, and fetal-maternal hemorrhage testing is recommended (Obstet Gynecol. 2009;113[3]:748-61). Recent data show that each of these four components is valuable and should be considered the basic work-up for stillbirth.
Risks and causes
Pregnancy history was the strongest baseline risk factor for stillbirth in an analysis of 614 stillbirths and 1,816 live births in the SCRN’s population-based, case-control study conducted between 2006 and 2008. The SCRN was initiated by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in 2003. This critical population-based study was conducted at 59 U.S. tertiary care and community hospitals in five catchment areas and has been analyzed in more than 15 published reports.
Women with a previous stillbirth have been known to be at 5- to 10-fold increased risk of a recurrence of stillbirth, and the SCRN findings confirmed this. The study added to our knowledge, however, with the finding that even a prior pregnancy loss at less than 20 weeks’ gestation increased the risk for stillbirth.
Other risk factors identified in the study, in addition to race, included having a multifetal pregnancy (adjusted odds ratio of 4.59), diabetes (AOR of 2.50), maternal age of 40 years or older (AOR of 2.41), maternal AB blood type (AOR of 1.96, compared with type O), a history of drug addiction (AOR of 2.08), smoking during the 3 months prior to pregnancy (AOR of 1.55-1.57, depending on amount), and being unmarried and not cohabitating (AOR of 1.69). Regarding racial disparity, the study showed that elevated risk of stillbirth for non-Hispanic blacks occurred predominantly prior to 24 weeks of gestation.
As in prior research, overweight and obesity also conferred elevated risks in the SCRN study (AORs of 1.43 and 1.72, respectively), and these risks were not explained by either diabetes or hypertension (JAMA. 2011;306:2469-79).
The use of assisted reproductive technology was not included in the study’s multivariate model, but previous research has shown a fourfold increased risk of stillbirth for singleton IVF/ICSI pregnancies. The reason is unclear, but the risk appears to be more related to IVF/ICSI rather than the underlying infertility (Hum Reprod. 2010 May;25[5]:1312-6).
A previous preterm or small-for-gestational-age birth has also been shown in prior research to be a significant risk factor for stillbirth. Less clear is the role of previous cesarean delivery in stillbirth risk. An association has been demonstrated in several studies, however, including one involving about 180,000 singleton pregnancies of 23 or more weeks’ gestation. Women in this cohort who had a previous cesarean delivery had a 1.3-fold increased risk of antepartum stillbirth, after controlling for important factors such as race, body mass index (BMI), and maternal disease (Obstet Gynecol. 2010 Nov;116[5]:1119-26).
In another analysis of the SCRN study looking specifically at causes of stillbirth, a “probable” cause of death was found in 61% of cases and a “possible or probable” cause of death in more than 76% of cases. The most common causes were obstetric complications (29.3%), placental abnormalities (23.6%), fetal genetic/structural abnormalities (13.7%), infection (12.9%), umbilical cord abnormalities (10.4%), hypertensive disorders (9.2%), and other maternal medical conditions (7.8%).
A higher proportion of stillbirths in non-Hispanic black women, compared with non-Hispanic white women and Hispanic women was associated with obstetric complications (43.5%) and infections (25.2%). This finding combined with the finding that stillbirth in black women often occurs at less than 24 weeks’ gestation suggests that measures aimed at reducing the rate of spontaneous preterm birth in black women could potentially reduce the rate of stillbirth as well (JAMA. 2011 Dec 14;306[22]:2459-68).
Work-up and prevention
Prevention of stillbirth requires that we identify the women at highest risk, and thus far this ability still eludes us. Apart from occurrence of previous stillbirth or pregnancy loss, other risk factors have had limited predictive value in the SCRN analyses and other research.
Biomarkers such as a low PAPP-A during the first trimester and a high AFP in the second trimester – as well as Doppler imaging of the uterine artery – have also been associated with stillbirth, but again, the positive predictive value has been shown to be low (Clin Obstet Gynecol. 2010 Sep;53[3]:597-606). More research is needed to determine if some combination of biochemical markers, imaging, and other risk factors can predict which women are at highest risk.
In the meantime, attention can be paid – in the preconception period if possible – to modifiable risk factors such as maternal obesity, diabetes, and smoking. About 10% of stillbirths are associated with maternal conditions such as hypertension and diabetes, and late stillbirths in particular (28 weeks or later) are associated with maternal medical conditions that are potentially preventable.
Normalization of prepregnancy weight should be a goal, since the overall risk of stillbirth appears to increase independently with increasing BMI. Glycemic control should also be achieved: A recent meta-analysis of preconception and prenatal care of diabetic women estimated “conservatively” that 10% of diabetes-associated stillbirths could be prevented with early detection and glycemic control (BMC Public Health. 2011;11 Suppl 3:S2). Research has also shown that women who quit smoking between their first and second pregnancy reduce their stillbirth risk to that of nonsmokers in the second pregnancy (BJOG. 2007 Jun;114[6]:699-704).
When stillbirth happens, a thorough work-up is recommended in order to counsel for future pregnancies and decrease the risk of recurrence. Evaluations for causes of stillbirth are too often incomplete in the United States for various reasons, including emotional, cultural, and resource factors. Even if a cause is not found, many families appreciate knowing that every effort has been made to determine a cause of death.
Four components of evaluation – autopsy, placental examination, karyotype or microarray analysis, and fetal-maternal hemorrhage testing – have proven to be high-yield tests when performed in all cases of stillbirth.
In the SCRN study, of 512 stillbirths undergoing a complete evaluation, 66.4% had a positive result – defined as abnormalities contributing to a probable or possible cause – for at least one of the first three tests (JAMA. 2011 Dec 14;306[22]:2459-68).
A Dutch study of 1,025 stillbirths similarly demonstrated that all four tests are justified. A test was defined as valuable in this study if it established or excluded a cause of stillbirth. Placental examination was determined to be the most valuable test, helping to determine a cause of death in 95.7% of cases. Autopsy was valuable 72.6% of the time, and cytogenetic analysis was valuable in 29% of cases.
Kleihauer-Betke testing for fetal-maternal hemorrhage was positive in 11.9% of women. However, fetal maternal hemorrhage was considered the cause of death in only 1.3%.of cases because, beyond a positive Kleihauer-Betke test, evidence of fetal anemia confirmed by placental examination and/or autopsy was required for hemorrhage to be considered the cause of death (Am. J. Obstet. Gynecol. 2012;206:53.e1-12). Because Kleihauer-Betke testing is ideally performed before induction, authors of both the SCRN study and the Dutch study believe it is a valuable test to be offered in all cases.
In both studies, the yield of other stillbirth diagnostic tests (for example, maternal serology, hormone assessment, and toxicology screen) was low, indicating that these tests are considered sequential and can be performed only when the clinical history or findings of the four core tests raise suspicion of particular potential causes. Antinuclear antibody testing and TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers have an extremely low yield and are generally not useful.
For detecting genetic abnormalities after stillbirth, it appears that microarray analysis is superior to karyotype analysis. In a SCRN analysis of samples from 532 stillbirths, microarray yielded results more often and identified more genetic abnormalities. Unlike karyotype, it does not require live cells, which makes it preferable for stillbirth evaluation (N Engl J Med. 2012 Dec 6;367[23]:2185-93).
Current research
One of the more significant studies underway on prevention is looking at labor induction as an intervention for reducing stillbirths and improving other perinatal outcomes. The ARRIVE trial (“A Randomized Trial of Induction Versus Expectant Management”), currently in the recruitment stage, will examine outcomes after induction at 39 weeks’ gestation, compared with expectant management in 6,000 patients (clinicaltrials.gov/ct2/show/NCT01990612).
Common wisdom informed by retrospective cohort studies has long told us that inducing labor prior to 41 weeks’ gestation is associated with a higher risk of cesarean delivery in nulliparous women. However, recent observational data have suggested that women whose labor is induced actually have fewer cesarean deliveries and better perinatal outcomes, including a lower risk of stillbirth (AJOG 2012;207:502.e1-8).
In addition, a meta-analysis published in 2014, as the ARRIVE trial was taking shape, reported a 12% reduction in cesarean delivery, and a reduced risk of stillbirth, among women whose labor was induced. The initial cervical score did not impact the main findings (CMAJ. 2014 Jun 10;186[9]:665-73). If these findings are confirmed in the ARRIVE trial, we could see a new opportunity for stillbirth prevention.
Another ongoing study of 10,000 singleton pregnancies – the Nulliparous Pregnancy Outcomes: Monitoring Mothers-to-Be (nuMoM2b) study – may also lead to prevention strategies in women for whom the current pregnancy will lead to their first delivery. Among the questions being examined in this eight-site study are whether sleep-disordered breathing, or apnea, and a supine sleep position are risk factors for adverse pregnancy outcomes including stillbirth.
Supine sleeping in the last month of pregnancy was strongly associated with stillbirth in a recent analysis from the Sydney Stillbirth Study (Obstet Gynecol. 2015 Feb;125[2]:347-55), and an early analysis of a nuMoM2b subset has shown associations between sleep-disordered breathing in midpregnancy and the development of hypertensive disorders of pregnancy, and between sleep-disordered breathing in early- and mid-pregnancy and gestational diabetes (Am J Obstet Gynecol. 2015;212:S424-425).
The possible role of low-dose aspirin in preventing stillbirth also needs more exploration. A recent randomized trial of women attempting to become pregnant after having had one or two prior pregnancy losses found no difference overall in live birth rates between those who took low-dose aspirin and those assigned to placebo. However, there was one subgroup – women with a single loss at less than 20 weeks’ gestation during the previous year – in which live birth rates were higher in the aspirin group (Lancet. 2014 Jul 5;384[9937]:29-36). More research is necessary to determine if low-dose aspirin administration in women with a previous stillbirth improves pregnancy outcome.
Dr. Reddy is a member at the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. She is a board-certified ob.gyn. and maternal-fetal medicine specialist. She is the program scientist for the Maternal-Fetal Medicine Units Network and for the Stillbirth Collaborative Research Network. The comments and views of the author do not necessarily represent the views of the NICHD.
Gene signatures aid diagnosis of acute respiratory infection etiology
Pathogen-specific host gene expression patterns accurately discriminated most noninfectious from infectious illnesses, and bacterial from viral causes of acute respiratory infection (ARI) in an observational study conducted in acute care settings.
The findings could have important implications for combating inappropriate antibiotic use and emerging antibiotic resistance, Dr. Ephraim L. Tsalik of the department of medicine at Duke University, Durham, N.C., and his colleagues reported online Jan. 20 in Science Translational Medicine.
The investigators analyzed peripheral whole-blood gene expression from 273 subjects with community-onset viral ARI (115 subjects), bacterial ARI (70 subjects), or noninfectious illness (88 subjects) who were seen in an emergency department, and from 44 healthy control subjects. Classifiers for bacterial ARI, viral ARI, and noninfectious causes of illness were developed, and were 87% accurate overall (Sci Transl Med. 2016;8[322]:322ra11. doi/ 10.1126/scitranslmed.aad6873).
“Bacterial ARI was identified in 83% of patients and excluded in 94% without bacterial infection. Viral ARI was identified in 90% and excluded in 92% of cases. Using the noninfectious illness classifier, infection was excluded in 86% of cases,” they wrote.
The classifiers were more accurate than procalcitonin – a widely used biomarker with some specificity for bacterial infection (86% vs. 78% accuracy in 238 available samples), and three published classifiers of bacterial vs. viral infection, and were validated in five publicly available data sets, they noted.
The gene signature patterns identified in the course of this study mark an important step toward development of a rapid blood test that could be used in clinics to guide appropriate treatment for ARIs, the investigators said.
Precision treatment of viruses
More precise ways to distinguish infections could reduce unnecessary antibiotic use and lead to more precise treatment of viruses, senior author Dr. Geoffrey S. Ginsburg, director of Duke’s Center for Applied Genomics & Precision Medicine, said in a press statement.
“Right now, we can give patients [oseltamivir] Tamiflu to help them recover from an influenza infection, but for most viral infections, the treatment is fluids and rest until it resolves. In the next 5-10 years, we will likely see new antiviral medications for common bugs like respiratory syncytial virus and even rhinovirus, and guiding treatment choices will be even more important,” he added.
Senior author Dr. Christopher W. Woods, also of Duke University, further explained in an interview that the findings are particularly exciting because “there isn’t much out there that accomplishes what we’ve done. So just about any level of accuracy is an improvement.” Further, he said the test is “a tool to aid in diagnosis, used in conjunction with the patient’s symptoms, examination, and other testing. So an imperfect test is okay, because it does not stand alone.”
Next steps include putting the assay on a testing platform that can be used at the point of care, and validating the findings in all populations, including infants, the elderly, and across ethnic groups, he said.
“The work is ongoing, and we expect to have results available within the course of an outpatient visit in the near future,” Dr. Woods, also a professor of medicine and global health, added, noting that efforts also are underway to “expand the repertoire of this approach to many different types of viral and bacterial infections and also to fungal infections, and to address the challenges of critically ill patients in intensive care units.”
This study was supported by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs Office of Research and Development, and an in-kind contribution from bioMérieux. The authors reported having no relevant competing interests.
Pathogen-specific host gene expression patterns accurately discriminated most noninfectious from infectious illnesses, and bacterial from viral causes of acute respiratory infection (ARI) in an observational study conducted in acute care settings.
The findings could have important implications for combating inappropriate antibiotic use and emerging antibiotic resistance, Dr. Ephraim L. Tsalik of the department of medicine at Duke University, Durham, N.C., and his colleagues reported online Jan. 20 in Science Translational Medicine.
The investigators analyzed peripheral whole-blood gene expression from 273 subjects with community-onset viral ARI (115 subjects), bacterial ARI (70 subjects), or noninfectious illness (88 subjects) who were seen in an emergency department, and from 44 healthy control subjects. Classifiers for bacterial ARI, viral ARI, and noninfectious causes of illness were developed, and were 87% accurate overall (Sci Transl Med. 2016;8[322]:322ra11. doi/ 10.1126/scitranslmed.aad6873).
“Bacterial ARI was identified in 83% of patients and excluded in 94% without bacterial infection. Viral ARI was identified in 90% and excluded in 92% of cases. Using the noninfectious illness classifier, infection was excluded in 86% of cases,” they wrote.
The classifiers were more accurate than procalcitonin – a widely used biomarker with some specificity for bacterial infection (86% vs. 78% accuracy in 238 available samples), and three published classifiers of bacterial vs. viral infection, and were validated in five publicly available data sets, they noted.
The gene signature patterns identified in the course of this study mark an important step toward development of a rapid blood test that could be used in clinics to guide appropriate treatment for ARIs, the investigators said.
Precision treatment of viruses
More precise ways to distinguish infections could reduce unnecessary antibiotic use and lead to more precise treatment of viruses, senior author Dr. Geoffrey S. Ginsburg, director of Duke’s Center for Applied Genomics & Precision Medicine, said in a press statement.
“Right now, we can give patients [oseltamivir] Tamiflu to help them recover from an influenza infection, but for most viral infections, the treatment is fluids and rest until it resolves. In the next 5-10 years, we will likely see new antiviral medications for common bugs like respiratory syncytial virus and even rhinovirus, and guiding treatment choices will be even more important,” he added.
Senior author Dr. Christopher W. Woods, also of Duke University, further explained in an interview that the findings are particularly exciting because “there isn’t much out there that accomplishes what we’ve done. So just about any level of accuracy is an improvement.” Further, he said the test is “a tool to aid in diagnosis, used in conjunction with the patient’s symptoms, examination, and other testing. So an imperfect test is okay, because it does not stand alone.”
Next steps include putting the assay on a testing platform that can be used at the point of care, and validating the findings in all populations, including infants, the elderly, and across ethnic groups, he said.
“The work is ongoing, and we expect to have results available within the course of an outpatient visit in the near future,” Dr. Woods, also a professor of medicine and global health, added, noting that efforts also are underway to “expand the repertoire of this approach to many different types of viral and bacterial infections and also to fungal infections, and to address the challenges of critically ill patients in intensive care units.”
This study was supported by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs Office of Research and Development, and an in-kind contribution from bioMérieux. The authors reported having no relevant competing interests.
Pathogen-specific host gene expression patterns accurately discriminated most noninfectious from infectious illnesses, and bacterial from viral causes of acute respiratory infection (ARI) in an observational study conducted in acute care settings.
The findings could have important implications for combating inappropriate antibiotic use and emerging antibiotic resistance, Dr. Ephraim L. Tsalik of the department of medicine at Duke University, Durham, N.C., and his colleagues reported online Jan. 20 in Science Translational Medicine.
The investigators analyzed peripheral whole-blood gene expression from 273 subjects with community-onset viral ARI (115 subjects), bacterial ARI (70 subjects), or noninfectious illness (88 subjects) who were seen in an emergency department, and from 44 healthy control subjects. Classifiers for bacterial ARI, viral ARI, and noninfectious causes of illness were developed, and were 87% accurate overall (Sci Transl Med. 2016;8[322]:322ra11. doi/ 10.1126/scitranslmed.aad6873).
“Bacterial ARI was identified in 83% of patients and excluded in 94% without bacterial infection. Viral ARI was identified in 90% and excluded in 92% of cases. Using the noninfectious illness classifier, infection was excluded in 86% of cases,” they wrote.
The classifiers were more accurate than procalcitonin – a widely used biomarker with some specificity for bacterial infection (86% vs. 78% accuracy in 238 available samples), and three published classifiers of bacterial vs. viral infection, and were validated in five publicly available data sets, they noted.
The gene signature patterns identified in the course of this study mark an important step toward development of a rapid blood test that could be used in clinics to guide appropriate treatment for ARIs, the investigators said.
Precision treatment of viruses
More precise ways to distinguish infections could reduce unnecessary antibiotic use and lead to more precise treatment of viruses, senior author Dr. Geoffrey S. Ginsburg, director of Duke’s Center for Applied Genomics & Precision Medicine, said in a press statement.
“Right now, we can give patients [oseltamivir] Tamiflu to help them recover from an influenza infection, but for most viral infections, the treatment is fluids and rest until it resolves. In the next 5-10 years, we will likely see new antiviral medications for common bugs like respiratory syncytial virus and even rhinovirus, and guiding treatment choices will be even more important,” he added.
Senior author Dr. Christopher W. Woods, also of Duke University, further explained in an interview that the findings are particularly exciting because “there isn’t much out there that accomplishes what we’ve done. So just about any level of accuracy is an improvement.” Further, he said the test is “a tool to aid in diagnosis, used in conjunction with the patient’s symptoms, examination, and other testing. So an imperfect test is okay, because it does not stand alone.”
Next steps include putting the assay on a testing platform that can be used at the point of care, and validating the findings in all populations, including infants, the elderly, and across ethnic groups, he said.
“The work is ongoing, and we expect to have results available within the course of an outpatient visit in the near future,” Dr. Woods, also a professor of medicine and global health, added, noting that efforts also are underway to “expand the repertoire of this approach to many different types of viral and bacterial infections and also to fungal infections, and to address the challenges of critically ill patients in intensive care units.”
This study was supported by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs Office of Research and Development, and an in-kind contribution from bioMérieux. The authors reported having no relevant competing interests.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: Pathogen-specific host gene expression patterns accurately discriminated most noninfectious from infectious illnesses, and bacterial from viral causes of acute respiratory infection (ARI) in an observational study.
Major finding: Classifiers for bacterial ARI, viral ARI, and noninfectious causes of illness were 87% accurate overall.
Data source: An observational cohort study involving 273 patients and 44 controls.
Disclosures: This study was supported by the U.S. Defense Advanced Research Projects Agency, the National Institutes of Health, the Agency for Healthcare Research and Quality, the U.S. Department of Veterans Affairs Office of Research and Development, and an in-kind contribution from bioMérieux. The authors reported having no relevant competing interests..
Everolimus is effective across diverse patients with GI neuroendocrine tumors
Everolimus improves outcomes in patients with advanced, progressive neuroendocrine tumors of gastrointestinal (GI) or unknown origin regardless of primary location and prior therapy, according to new subgroup analyses of the RADIANT-4 trial.
The phase III trial is the largest of its type in patients with nonfunctioning GI tract or lung neuroendocrine tumors. The subgroup findings for those whose tumors originated in the GI tract or an unknown site (but suspected to be GI) were presented in a presscast held in advance of the Gastrointestinal Cancers Symposium.
Compared with placebo, everolimus prolonged progression-free survival by 6-9 months, corresponding to a 46%-48% relative reduction in the risk of progression or death, reported lead study author Dr. Simron Singh of Sunnybrook’s Odette Cancer Centre in Toronto. Benefit was similar regardless of whether patients had midgut or non-midgut tumors, and whether they had previously received a somatostatin analog or not.
“In my opinion, this study in advanced, progressive neuroendocrine patients [shows] an effective, new and exciting treatment option in a disease where we’ve had very few treatments to date,” Dr. Singh said ahead of the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
ASCO expert and presscast moderator Dr. Smitha Krishnamurthi of Case Western Reserve University, Cleveland, agreed, saying that everolimus could help address an unmet need in this disease.
“Patients with GI neuroendocrine tumors have had very few treatment options. Once they have progressed on somatostatin analogues, there really are no good systemic treatments,” she said. “So this finding is very important, that the mTOR inhibitor everolimus has demonstrated an improvement in risk of progression by over 40% and with very little severe toxicity. This is a welcome finding for these patients who have limited systemic treatment options.”
Patients enrolled in RADIANT-4 had lung, GI, or unknown-origin neuroendocrine tumors that had progressed on other therapies, including somatostatin analogs, surgery, or chemotherapy.
They were randomly assigned in 2:1 ratio to receive everolimus (Afinitor) or placebo, each in addition to best supportive care. Everolimus is currently approved by the Food and Drug Administration for the treatment of pancreatic neuroendocrine tumors, as well as breast and kidney cancer, and subependymal giant cell astrocytoma.
Results for the entire trial population have been previously reported and showed that everolimus prolonged progression-free survival by 7.1 months, reducing the risk of events by 52% (Lancet. 2015 Dec 15. doi.org/10.1016/S0140-6736[15]01234-9).
The new subgroup analyses were restricted to the patients with tumors originating in the GI tract (n =175) or an unknown site generally thought to be the GI tract (n = 36).
Among the group with GI tumors, median progression-free survival was 13.1 months with everolimus versus 5.4 months with placebo, Dr. Singh reported. Among the group with tumors of unknown origin, it was 13.6 and 7.5 months, respectively.
Relative to placebo, everolimus prolonged progression-free survival by 6.41 months, reducing the risk of events by 29%, in patients whose tumors originated in the midgut (duodenum, ileum, jejunum, cecum, or appendix). The relative benefit was 6.17 months, with a reduction in the risk of events of 73%, in patients whose tumors originated in non-midgut sites (stomach, colon, and rectum).
In addition, everolimus prolonged progression-free survival by 6.73 months, reducing the risk of events by 46%, in patients who had previously received somatostatin analogues, and by 9.07 months, reducing the risk by 48%, in patients who had not received these agents.
The safety profile of everolimus was consistent with that expected based on the use of this agent in other patient populations, according to Dr. Singh. The most common adverse events were stomatitis, infections, diarrhea, peripheral edema, and fatigue. No new safety signals were seen.
Dr. Singh disclosed that he receives honoraria from, has a consulting or advisory role with, and receives research funding (institutional) and travel, accommodations, and expenses from Novartis. The study received funding from Novartis Pharmaceuticals.
Everolimus improves outcomes in patients with advanced, progressive neuroendocrine tumors of gastrointestinal (GI) or unknown origin regardless of primary location and prior therapy, according to new subgroup analyses of the RADIANT-4 trial.
The phase III trial is the largest of its type in patients with nonfunctioning GI tract or lung neuroendocrine tumors. The subgroup findings for those whose tumors originated in the GI tract or an unknown site (but suspected to be GI) were presented in a presscast held in advance of the Gastrointestinal Cancers Symposium.
Compared with placebo, everolimus prolonged progression-free survival by 6-9 months, corresponding to a 46%-48% relative reduction in the risk of progression or death, reported lead study author Dr. Simron Singh of Sunnybrook’s Odette Cancer Centre in Toronto. Benefit was similar regardless of whether patients had midgut or non-midgut tumors, and whether they had previously received a somatostatin analog or not.
“In my opinion, this study in advanced, progressive neuroendocrine patients [shows] an effective, new and exciting treatment option in a disease where we’ve had very few treatments to date,” Dr. Singh said ahead of the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
ASCO expert and presscast moderator Dr. Smitha Krishnamurthi of Case Western Reserve University, Cleveland, agreed, saying that everolimus could help address an unmet need in this disease.
“Patients with GI neuroendocrine tumors have had very few treatment options. Once they have progressed on somatostatin analogues, there really are no good systemic treatments,” she said. “So this finding is very important, that the mTOR inhibitor everolimus has demonstrated an improvement in risk of progression by over 40% and with very little severe toxicity. This is a welcome finding for these patients who have limited systemic treatment options.”
Patients enrolled in RADIANT-4 had lung, GI, or unknown-origin neuroendocrine tumors that had progressed on other therapies, including somatostatin analogs, surgery, or chemotherapy.
They were randomly assigned in 2:1 ratio to receive everolimus (Afinitor) or placebo, each in addition to best supportive care. Everolimus is currently approved by the Food and Drug Administration for the treatment of pancreatic neuroendocrine tumors, as well as breast and kidney cancer, and subependymal giant cell astrocytoma.
Results for the entire trial population have been previously reported and showed that everolimus prolonged progression-free survival by 7.1 months, reducing the risk of events by 52% (Lancet. 2015 Dec 15. doi.org/10.1016/S0140-6736[15]01234-9).
The new subgroup analyses were restricted to the patients with tumors originating in the GI tract (n =175) or an unknown site generally thought to be the GI tract (n = 36).
Among the group with GI tumors, median progression-free survival was 13.1 months with everolimus versus 5.4 months with placebo, Dr. Singh reported. Among the group with tumors of unknown origin, it was 13.6 and 7.5 months, respectively.
Relative to placebo, everolimus prolonged progression-free survival by 6.41 months, reducing the risk of events by 29%, in patients whose tumors originated in the midgut (duodenum, ileum, jejunum, cecum, or appendix). The relative benefit was 6.17 months, with a reduction in the risk of events of 73%, in patients whose tumors originated in non-midgut sites (stomach, colon, and rectum).
In addition, everolimus prolonged progression-free survival by 6.73 months, reducing the risk of events by 46%, in patients who had previously received somatostatin analogues, and by 9.07 months, reducing the risk by 48%, in patients who had not received these agents.
The safety profile of everolimus was consistent with that expected based on the use of this agent in other patient populations, according to Dr. Singh. The most common adverse events were stomatitis, infections, diarrhea, peripheral edema, and fatigue. No new safety signals were seen.
Dr. Singh disclosed that he receives honoraria from, has a consulting or advisory role with, and receives research funding (institutional) and travel, accommodations, and expenses from Novartis. The study received funding from Novartis Pharmaceuticals.
Everolimus improves outcomes in patients with advanced, progressive neuroendocrine tumors of gastrointestinal (GI) or unknown origin regardless of primary location and prior therapy, according to new subgroup analyses of the RADIANT-4 trial.
The phase III trial is the largest of its type in patients with nonfunctioning GI tract or lung neuroendocrine tumors. The subgroup findings for those whose tumors originated in the GI tract or an unknown site (but suspected to be GI) were presented in a presscast held in advance of the Gastrointestinal Cancers Symposium.
Compared with placebo, everolimus prolonged progression-free survival by 6-9 months, corresponding to a 46%-48% relative reduction in the risk of progression or death, reported lead study author Dr. Simron Singh of Sunnybrook’s Odette Cancer Centre in Toronto. Benefit was similar regardless of whether patients had midgut or non-midgut tumors, and whether they had previously received a somatostatin analog or not.
“In my opinion, this study in advanced, progressive neuroendocrine patients [shows] an effective, new and exciting treatment option in a disease where we’ve had very few treatments to date,” Dr. Singh said ahead of the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.
ASCO expert and presscast moderator Dr. Smitha Krishnamurthi of Case Western Reserve University, Cleveland, agreed, saying that everolimus could help address an unmet need in this disease.
“Patients with GI neuroendocrine tumors have had very few treatment options. Once they have progressed on somatostatin analogues, there really are no good systemic treatments,” she said. “So this finding is very important, that the mTOR inhibitor everolimus has demonstrated an improvement in risk of progression by over 40% and with very little severe toxicity. This is a welcome finding for these patients who have limited systemic treatment options.”
Patients enrolled in RADIANT-4 had lung, GI, or unknown-origin neuroendocrine tumors that had progressed on other therapies, including somatostatin analogs, surgery, or chemotherapy.
They were randomly assigned in 2:1 ratio to receive everolimus (Afinitor) or placebo, each in addition to best supportive care. Everolimus is currently approved by the Food and Drug Administration for the treatment of pancreatic neuroendocrine tumors, as well as breast and kidney cancer, and subependymal giant cell astrocytoma.
Results for the entire trial population have been previously reported and showed that everolimus prolonged progression-free survival by 7.1 months, reducing the risk of events by 52% (Lancet. 2015 Dec 15. doi.org/10.1016/S0140-6736[15]01234-9).
The new subgroup analyses were restricted to the patients with tumors originating in the GI tract (n =175) or an unknown site generally thought to be the GI tract (n = 36).
Among the group with GI tumors, median progression-free survival was 13.1 months with everolimus versus 5.4 months with placebo, Dr. Singh reported. Among the group with tumors of unknown origin, it was 13.6 and 7.5 months, respectively.
Relative to placebo, everolimus prolonged progression-free survival by 6.41 months, reducing the risk of events by 29%, in patients whose tumors originated in the midgut (duodenum, ileum, jejunum, cecum, or appendix). The relative benefit was 6.17 months, with a reduction in the risk of events of 73%, in patients whose tumors originated in non-midgut sites (stomach, colon, and rectum).
In addition, everolimus prolonged progression-free survival by 6.73 months, reducing the risk of events by 46%, in patients who had previously received somatostatin analogues, and by 9.07 months, reducing the risk by 48%, in patients who had not received these agents.
The safety profile of everolimus was consistent with that expected based on the use of this agent in other patient populations, according to Dr. Singh. The most common adverse events were stomatitis, infections, diarrhea, peripheral edema, and fatigue. No new safety signals were seen.
Dr. Singh disclosed that he receives honoraria from, has a consulting or advisory role with, and receives research funding (institutional) and travel, accommodations, and expenses from Novartis. The study received funding from Novartis Pharmaceuticals.
FROM THE GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point: Everolimus reduces the risk of progression or death across subgroups of patients who have advanced, progressive neuroendocrine tumors arising in the GI tract or an unknown site.
Major finding: Compared with placebo, everolimus prolonged median progression-free survival by 6-9 months in patients with midgut and non-midgut tumors, and in patients who had and had not received somatostatin analogues.
Data source: A subgroups analysis of a phase III trial among 211 patients with advanced, progressive nonfunctioning neuroendocrine tumors originating in the GI tract or an unknown site (RADIANT-4 trial).
Disclosures: Dr. Singh disclosed that he receives honoraria from, has a consulting or advisory role with, and receives research funding (institutional) and travel, accommodations, and expenses from Novartis. The study received funding from Novartis Pharmaceuticals.