L. D. Britt, MD, MPH, DSc(Hon), FACS, FCCM, FRCSEng(Hon), FRCSEd(Hon), FWACS(Hon), FRCSI(Hon), FCS(SA)(Hon), FRCSGlasg(Hon), Henry Ford Professor and Edward Brickhouse Chairman, department of surgery, Eastern Virginia Medical School, Norfolk, and a Past-President of the American College of Surgeons (ACS), was recently awarded a multimillion-dollar National Institutes of Health (NIH) research grant. The grant will be used to develop strategies to address health care disparities in the various surgical specialties. Specifically, the emphasis of this research is “to determine the specific measures of health care disparities in the various surgical specialties in order to develop targeted interventions to mitigate such disparities,” said Dr. Britt, principal investigator of the research project.

The NIH R01 grants are among the most competitive awards in scientific research. Dr. Britt’s research team comprises experts in the field who work in medical organizations and academic institutions, such as the ACS; Harvard Medical School, Boston, MA; and the University of California, Los Angeles.

Dr. Britt has dedicated his career to patient care and addressing the multifaceted disparities in health care, and he believes that this research grant is a pivotal step toward countering one of the greatest challenges facing this country. He is particularly thankful for the unwavering support of David B. Hoyt, MD, FACS, ACS Executive Director; the Board of Regents; and the ACS Committee on Health Care Disparities, which he chairs. Adil Haider, MD, MPH, FACS, professor and director of the Center for Surgery and Public Health, Harvard Medical School, serves as Vice-Chair of the committee.

“This is a big step for the American College of Surgeons,” Dr. Britt said. “With its 100-plus year history of using data to address quality of care in surgery, if the College, in collaboration with the NIH, can’t solve this problem, no one can.”

Dr. Britt added that he anticipates that the College’s efforts to address disparities in health care with the help of the NIH will serve as a template for other professional organizations so that all patients have access to the services they need, from primary care to obstetrics-gynecology, and from cardiology to psychiatry. “Dr. Hoyt and I hope this is the start of movement to address health care disparities in all specialties, but it starts with the College.”

L. D. Britt, MD, MPH, DSc(Hon), FACS, FCCM, FRCSEng(Hon), FRCSEd(Hon), FWACS(Hon), FRCSI(Hon), FCS(SA)(Hon), FRCSGlasg(Hon), Henry Ford Professor and Edward Brickhouse Chairman, department of surgery, Eastern Virginia Medical School, Norfolk, and a Past-President of the American College of Surgeons (ACS), was recently awarded a multimillion-dollar National Institutes of Health (NIH) research grant. The grant will be used to develop strategies to address health care disparities in the various surgical specialties. Specifically, the emphasis of this research is “to determine the specific measures of health care disparities in the various surgical specialties in order to develop targeted interventions to mitigate such disparities,” said Dr. Britt, principal investigator of the research project.

The NIH R01 grants are among the most competitive awards in scientific research. Dr. Britt’s research team comprises experts in the field who work in medical organizations and academic institutions, such as the ACS; Harvard Medical School, Boston, MA; and the University of California, Los Angeles.

Dr. Britt has dedicated his career to patient care and addressing the multifaceted disparities in health care, and he believes that this research grant is a pivotal step toward countering one of the greatest challenges facing this country. He is particularly thankful for the unwavering support of David B. Hoyt, MD, FACS, ACS Executive Director; the Board of Regents; and the ACS Committee on Health Care Disparities, which he chairs. Adil Haider, MD, MPH, FACS, professor and director of the Center for Surgery and Public Health, Harvard Medical School, serves as Vice-Chair of the committee.

“This is a big step for the American College of Surgeons,” Dr. Britt said. “With its 100-plus year history of using data to address quality of care in surgery, if the College, in collaboration with the NIH, can’t solve this problem, no one can.”

Dr. Britt added that he anticipates that the College’s efforts to address disparities in health care with the help of the NIH will serve as a template for other professional organizations so that all patients have access to the services they need, from primary care to obstetrics-gynecology, and from cardiology to psychiatry. “Dr. Hoyt and I hope this is the start of movement to address health care disparities in all specialties, but it starts with the College.”

L. D. Britt, MD, MPH, DSc(Hon), FACS, FCCM, FRCSEng(Hon), FRCSEd(Hon), FWACS(Hon), FRCSI(Hon), FCS(SA)(Hon), FRCSGlasg(Hon), Henry Ford Professor and Edward Brickhouse Chairman, department of surgery, Eastern Virginia Medical School, Norfolk, and a Past-President of the American College of Surgeons (ACS), was recently awarded a multimillion-dollar National Institutes of Health (NIH) research grant. The grant will be used to develop strategies to address health care disparities in the various surgical specialties. Specifically, the emphasis of this research is “to determine the specific measures of health care disparities in the various surgical specialties in order to develop targeted interventions to mitigate such disparities,” said Dr. Britt, principal investigator of the research project.

The NIH R01 grants are among the most competitive awards in scientific research. Dr. Britt’s research team comprises experts in the field who work in medical organizations and academic institutions, such as the ACS; Harvard Medical School, Boston, MA; and the University of California, Los Angeles.

Dr. Britt has dedicated his career to patient care and addressing the multifaceted disparities in health care, and he believes that this research grant is a pivotal step toward countering one of the greatest challenges facing this country. He is particularly thankful for the unwavering support of David B. Hoyt, MD, FACS, ACS Executive Director; the Board of Regents; and the ACS Committee on Health Care Disparities, which he chairs. Adil Haider, MD, MPH, FACS, professor and director of the Center for Surgery and Public Health, Harvard Medical School, serves as Vice-Chair of the committee.

“This is a big step for the American College of Surgeons,” Dr. Britt said. “With its 100-plus year history of using data to address quality of care in surgery, if the College, in collaboration with the NIH, can’t solve this problem, no one can.”

Dr. Britt added that he anticipates that the College’s efforts to address disparities in health care with the help of the NIH will serve as a template for other professional organizations so that all patients have access to the services they need, from primary care to obstetrics-gynecology, and from cardiology to psychiatry. “Dr. Hoyt and I hope this is the start of movement to address health care disparities in all specialties, but it starts with the College.”

The Food and Drug Administration has approved Cyltezo (adalimumab-adbm) for multiple conditions.

Cyltezo is an injectable tumor necrosis factor blocker, and is a biosimilar to adalimumab (Humira). The drug is indicated to treat moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderate to severe active Crohn’s disease, moderate to severe active ulcerative colitis, moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older, and moderate to severe plaque psoriasis.

[email protected]

The Food and Drug Administration has approved Cyltezo (adalimumab-adbm) for multiple conditions.

Cyltezo is an injectable tumor necrosis factor blocker, and is a biosimilar to adalimumab (Humira). The drug is indicated to treat moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderate to severe active Crohn’s disease, moderate to severe active ulcerative colitis, moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older, and moderate to severe plaque psoriasis.

[email protected]

The Food and Drug Administration has approved Cyltezo (adalimumab-adbm) for multiple conditions.

Cyltezo is an injectable tumor necrosis factor blocker, and is a biosimilar to adalimumab (Humira). The drug is indicated to treat moderate to severe active rheumatoid arthritis, active psoriatic arthritis, active ankylosing spondylitis, moderate to severe active Crohn’s disease, moderate to severe active ulcerative colitis, moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older, and moderate to severe plaque psoriasis.

[email protected]

Pembrolizumab monotherapy showed durable antitumor activity in extensive-stage small-cell lung cancer, and its safety profile resembled that in other tumor types, based on the results of the phase 1b KEYNOTE-028 study of 24 patients.

One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.

Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.

The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”

Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.

Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.

Pembrolizumab monotherapy showed durable antitumor activity in extensive-stage small-cell lung cancer, and its safety profile resembled that in other tumor types, based on the results of the phase 1b KEYNOTE-028 study of 24 patients.

One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.

Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.

The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”

Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.

Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.

Pembrolizumab monotherapy showed durable antitumor activity in extensive-stage small-cell lung cancer, and its safety profile resembled that in other tumor types, based on the results of the phase 1b KEYNOTE-028 study of 24 patients.

One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.

Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.

The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”

Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.

Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.

Take-Home Points

• When conservative treatments for SIS do not resolve symptoms, inflammation and pain can be reduced with use of subacromial CSI.

• Both anterior CSI and posterior CSI significantly improved pain and function for up to 6 months

• CSI combined with structured PT produced significant improvement in pain and function in patients with SIS, regardless of injection route used.

• Clinical response to CSI may not depend on injection accuracy.

• Clinicians should rely on their clinical acumen when selecting injection routes, as anterior and posterior are both beneficial.

Shoulder pain, a common clinical problem, occurs in 7% to 34% of the general population and in 21% of people older than 70 years.¹Subacromial impingement refers to shoulder pain resulting from mechanical impingement of the rotator cuff underneath the coracoacromial arch between the acromion and the humeral head.^2,3 Subacromial impingement syndrome (SIS) is the most common cause of shoulder pain, resulting in significant functional deficits and disability.³

Treatment options for SIS include conservative modalities such as use of nonsteroidal anti-inflammatory drugs, physical therapy (PT), and subacromial corticosteroid injections (CSIs). Studies have found short- and long-term improvement in pain, function, and range of motion after CSI.^4-8 Subacromial CSI can be administered through an anterior or a posterior route.^4,9 There have been several studies of the accuracy of anterior and posterior CSIs,^10-12 with 2 studies finding similar accuracy for these routes.^10,11 However, there may be a sex difference: In women, a posterior route may be less accurate than an anterior or a lateral route.¹²

Although the accuracy of anterior and posterior routes has been studied, their effect on clinical outcomes has not. We conducted a study to understand the effects of anterior and posterior CSIs on SIS. As one of the accuracy studies suggested anterior CSI is more accurate—the anterior route was theorized to provide easier access to the subacromial space¹²—we hypothesized patients treated with anterior CSI would have superior clinical outcomes 6 months after injection.^12,13

Materials and Methods

Study Participants and Randomization

After this study received Institutional Review Board approval, patients with shoulder pain of more than 3 months’ duration and consistent with SIS were screened for inclusion. Eligible patients had pain in the anterior biceps and over the top of the shoulder with overhead activities as well as one or more clinical findings on physical examination: Hawkins-Kennedy sign, Neer sign, painful arc, and infraspinatus pain (pain with external rotation).

Patients were excluded if their history included prior subacromial CSI, adhesive capsulitis (inability to passively abduct shoulder to 90° with scapular stabilization), calcific tendonitis, radiographic evidence of os acromiale, cervical radiculopathy, Spurling sign, neck pain, radiating arm pain or numbness, sensory deficits, or neck and upper extremity motor dysfunction. Also excluded were patients with full-thickness rotator cuff tear, weakness on arm elevation, positive "drop arm sign," or high-riding humerus on standing shoulder radiograph. Patients who had work-related injuries or who were involved in worker compensation were excluded as well.

Enrolled patients were randomly assigned (with use of a computer-based random number generator) to receive either anterior CSI or posterior CSI.

Injection Procedures

All patients were administered 5 mL of lidocaine 1% (without epinephrine) and 2 mL (80 mg) of triamcinolone by 2 board-certified orthopedic surgeons using a 22-gauge 1½-inch needle. For patients who received their subacromial CSI by the anterior route, the arm was held in 0° of abduction and 20° of external rotation. The needle was inserted medial to the humeral head, lateral to the coracoid process, beginning 1 cm inferior to the clavicle with the needle directed posteriorly and laterally toward the acromion.¹⁰ For patients who received their CSI by the posterior route, the arm was held in 0° of abduction, the posterolateral corner of the acromion was identified by palpation, and the needle was inserted 1 cm inferior and medial to this point with the needle directed anteriorly and laterally toward the acromion.^10,12 In both groups, the subacromial space was identified when a drop in pressure was felt during needle insertion. Accuracy was assessed post hoc by asking patients to grade their response to the injection on a visual analog scale (VAS); VAS score was used as a surrogate for improvement. All patients had a positive Neer test: Pain decreased with impingement maneuvers immediately after injection.

All patients were referred for PT provided according to an evidence-based rehabilitation protocol.¹⁴ This program emphasized range of motion with shoulder shrugs, scapular retraction, and pendulum exercises; flexibility with stretching exercises targeting the anterior and posterior aspects of the shoulder and cane stretching for forward elevation and external rotation; and strength with strengthening exercises involving the rotator cuff and scapular stabilizers.

Outcome Measures

Pain was measured with VAS scores and function with Single Assessment Numeric Evaluation (SANE) scores. The VAS is a validated outcome measure of pain intensity. A numeric version of the VAS was used: Patients selected the whole number, from 0 (no pain) to 10 (worst possible pain), that best reflected their pain intensity. On SANE, another validated outcome measure, patients rated their shoulder function as a percentage of normal, from 0% (no function possible) to 100% (perfect).¹⁵ Before injection, all patients were administered the VAS and SANE questionnaires to establish their baseline pain level and opinion of shoulder function. These measures were repeated 1, 3, and 6 months after injection. Telephone interviews were conducted at 1 month and 6 months. Patients were asked to return to clinic 3 months after injection as part of the standard of care. At 3 months, 47 (86%) of the 55 patients returned for follow-up and were administered the VAS and SANE questionnaires; the other 8 completed the questionnaires by telephone. At each time point, patients were asked to report on their participation in PT and/or adherence to their home exercise program.

Statistical Analysis

Power analysis performed with Student t test and a 2-sided level of P = .05 compared VAS pain scores between the anterior and posterior injection routes and found a mean (SD) difference of 1.4 (1.7).¹⁶ Power calculations made with nQuery Advisor Version 7.0 (Statistical Solutions) indicated a total sample size of 60 patients (30/group) would provide 80% power for detecting a significant difference assuming a 20% dropout rate.

Two-way mixed-model analysis of variance (ANOVA) was used to compare the anterior and posterior routes for statistical differences in both VAS pain scores and SANE function scores at baseline and 1, 3, and 6 months after injection. Likewise, time at baseline (just before injection)was compared with follow-up (1, 3, 6 months) with 2-way mixed-model ANOVA adjusting for anterior or posterior route. Multivariate analysis was performed to evaluate differences between baseline and 6-month follow-up with respect to anterior and posterior injection routes, controlling for age, sex, and body mass index (BMI) for VAS and SANE scores. Parametric testing methods were used for statistical analysis, which was performed with IBM SPSS Statistics Version 21.0 (IBM Corp). Significance was set at P < .05.

Results

Patient Characteristics

Of the 55 patients enrolled, 25 (46%) received anterior subacromial CSI and 30 (54%) received posterior CSI. All enrolled patients had a positive Neer impingement test immediately after injection. Mean (SD) age was 48 (9.3) years for anterior group patients and 48 (9.0) years for posterior group patients. There was no significant difference in age or BMI between the 2 groups (Table).

Five patients (9%) were excluded from the study after randomization and CSI: 2 for a full-thickness rotator cuff tear, 1 for a Bankart lesion, 1 for adhesive capsulitis, and 1 for a worker compensation claim.

One month after injection, 41 patients (75%) reported having engaged in PT as prescribed. Of the 47 patients (86%) who returned for the 3-month follow-up, 25 (46%) reported having engaged in PT between 1 month and 3 months after injection. Fourteen patients (26%) reported attending PT between 3 and 6 months post-injection.

Outcome Measures

Two-way repeated-measures ANOVA with age, sex, and BMI included as covariates revealed no significant differences in VAS scores between the anterior and posterior groups at any time point (P = .45). Both groups had highly significant pain reductions (anterior, F = 9.71, P < .001; posterior, F = 13.46, P < .001). Figure 1 shows mean VAS scores and significant reductions in pain 1, 3, and 6 months after injection (see asterisks for anterior and posterior groups; P < .001 for all). The groups had parallel rates of pain reduction over time, as indicated by a nonsignificant (P = .50) difference in slopes. These pain score reductions were significant for both injection routes and were independent of age, sex, and BMI (P > .05 for all).

Two-way repeated-measures ANOVA with age, sex, and BMI included as covariates revealed no significant differences in SANE scores between the anterior and posterior groups, except for a higher mean score in the anterior group at 3 months
(P = .02). There were no other group differences (P > .10 for all). Both groups had highly significant improvements in function (anterior, F = 17.34,
P < .001; posterior, F = 13.57, P < .001). Figure 2 shows mean SANE scores and significant improvement at 1, 3, and 6 months (see asterisks for anterior and posterior groups; P < .001 for all). The groups had parallel rates of improved function over time, as indicated by a nonsignificant (P = .51) difference in slopes. These function score improvements were significant for both injection routes and were independent of age, sex, and BMI (P > .05 for all).

From the results of this prospective randomized study, we concluded subacromial CSI significantly reduces pain and improves function regardless of route used. In addition, age, sex, and BMI do not significantly affect the efficacy of either anterior CSI or posterior CSI.

Discussion

In patients with SIS, anterior CSI and posterior CSI provided significant improvements in pain and function 1, 3, and 6 months after injection. These effects were independent of age, sex, BMI, and PT participation. There were no significant differences in outcomes between injection routes.

When conservative treatments for SIS do not resolve symptoms, inflammation and pain can be reduced with use of subacromial CSI.^4-8 Although clinical outcomes are inconsistent, CSI can be used to address SIS symptoms in appropriate patients. Specifically, Blair and colleagues⁶ found that, CSI consisting of 4 mL of lidocaine 1% (without epinephrine) and 2 mL (80 mg) of triamcinolone was effective in alleviating shoulder pain and improving shoulder range of motion. Other authors have similarly reported improved outcomes after subacromial injection and short-term follow-up with PT.^4,7,8 Our findings are consistent with these reports: CSI coupled with a structured rehabilitation program is effective in alleviating symptoms associated with acute or subacute SIS.

Numerous studies have found improved clinical outcomes after anterior CSI and after posterior CSI,^6-8 but no study has directly compared the clinical impact of anterior CSI with that of posterior CSI—which suggests injection route may not affect ultimate clinical outcomes.

CSI accuracy has been studied extensively.^10-12,17-20 Although 2 studies found similar accuracy for anterior and posterior routes,^10,11 there may be a sex difference: In women, a posterior route may be less accurate than an anterior or a lateral route.¹² Collectively, these studies expose the inherent difficulty in treating shoulder pain with localized subacromial injection. Therapy may fail because of errant needle positioning. Two prospective studies found improved clinical outcomes with successful delivery of medication into the subacromial space.^17,18 Poor clinical outcomes may result from inaccurate CSI.

In contrast to other clinical studies, our study found that injection route was not associated with differences in clinical response. In a prospective randomized clinical trial in which 75 patients received a subacromial injection, Marder and colleagues¹² found anterior routes 84% accurate and posterior routes 56% accurate; they concluded acromion anatomy and subacromial bursa anatomy make posterior injections more difficult. As theorized by Gruson and colleagues,¹³ with use of an anterior route, the needle enters inferior to the concavity of the acromion and provides easier access to the subacromial space. This idea is in line with Marder and colleagues’¹² conclusion that subacromial bursa anatomy provides a favorable environment for accurate CSI.

If accuracy is positively correlated with clinical improvement and anterior routes are more accurate, there should be a difference in response to posterior injections. Our results provide evidence that clinical response to CSI may not depend on injection accuracy. Perhaps merely placing the corticosteroid near the bursa is adequate for improving symptoms or perhaps some of the clinical improvement is due to the systemic effect of corticosteroids. These possibilities require further analysis.

Establishing the efficacy of CSI in SIS is difficult. The literature includes various study designs, different CSI indications and medication formulations, and varying emphasis on the role of organized PT. Rehabilitation has been found to alleviate joint pain by reducing inflammation,¹⁴ but data do not universally support this finding.^21,22 Nevertheless, use of PT might explain the divergence in clinical outcomes reported by Marder and colleagues,¹² who found anterior CSI more accurate than posterior CSI. In our practice, PT is recommended for all SIS patients, not only those who have CSI. Thus, our findings are framed within the context of successful CSI but may include patients who improved with PT alone. This issue raises the question of whether subacromial CSI should be guided by ultrasound. Ultrasound guidance can improve CSI accuracy and clinical outcomes,^23-25 though the value of this benefit is debated.²⁶

This study had several limitations. First, pain relief was patient reported. Second, the treatment plan involved CSI with PT but did not control for CSI used alone. PT, which is part of the standard of care for patients with SIS, added another degree of complexity to the study. Third, there may have been some variability in SIS severity (stage 1, 2, or 3). Fourth, although the study design controlled for various shoulder pathologies, advanced imaging, which could have provided diagnosis confirmation, was not available for all patients. Therefore, concurrent conditions may have confounded results. However, randomization was used to try to minimize this effect. Fifth, although injection routes were randomly assigned, the trial was not blinded. Sixth, the study was underpowered by 1 patient, as there was an estimated 20% dropout rate over 3 and 6 months of follow-up. However, we do not think our results were significantly affected.

Although more research is needed to fully describe the role of subacromial CSI in SIS, our study findings suggested that CSI using either an anterior or a posterior route creates a window of symptomatic relief in which patients may be able to engage in PT.

Conclusion

Both anterior CSI and posterior CSI significantly improved pain and function for up to 6 months. No differences were found between anterior and posterior CSIs. In the context of this study, CSI combined with structured PT produced significant improvement in pain and function in patients with SIS, regardless of injection route used. Clinicians should rely on their clinical acumen when selecting injection routes, as anterior and posterior are both beneficial.

Take-Home Points

• When conservative treatments for SIS do not resolve symptoms, inflammation and pain can be reduced with use of subacromial CSI.

• Both anterior CSI and posterior CSI significantly improved pain and function for up to 6 months

• CSI combined with structured PT produced significant improvement in pain and function in patients with SIS, regardless of injection route used.

• Clinical response to CSI may not depend on injection accuracy.

• Clinicians should rely on their clinical acumen when selecting injection routes, as anterior and posterior are both beneficial.

Shoulder pain, a common clinical problem, occurs in 7% to 34% of the general population and in 21% of people older than 70 years.¹Subacromial impingement refers to shoulder pain resulting from mechanical impingement of the rotator cuff underneath the coracoacromial arch between the acromion and the humeral head.^2,3 Subacromial impingement syndrome (SIS) is the most common cause of shoulder pain, resulting in significant functional deficits and disability.³

Treatment options for SIS include conservative modalities such as use of nonsteroidal anti-inflammatory drugs, physical therapy (PT), and subacromial corticosteroid injections (CSIs). Studies have found short- and long-term improvement in pain, function, and range of motion after CSI.^4-8 Subacromial CSI can be administered through an anterior or a posterior route.^4,9 There have been several studies of the accuracy of anterior and posterior CSIs,^10-12 with 2 studies finding similar accuracy for these routes.^10,11 However, there may be a sex difference: In women, a posterior route may be less accurate than an anterior or a lateral route.¹²

Although the accuracy of anterior and posterior routes has been studied, their effect on clinical outcomes has not. We conducted a study to understand the effects of anterior and posterior CSIs on SIS. As one of the accuracy studies suggested anterior CSI is more accurate—the anterior route was theorized to provide easier access to the subacromial space¹²—we hypothesized patients treated with anterior CSI would have superior clinical outcomes 6 months after injection.^12,13

Materials and Methods

Study Participants and Randomization

After this study received Institutional Review Board approval, patients with shoulder pain of more than 3 months’ duration and consistent with SIS were screened for inclusion. Eligible patients had pain in the anterior biceps and over the top of the shoulder with overhead activities as well as one or more clinical findings on physical examination: Hawkins-Kennedy sign, Neer sign, painful arc, and infraspinatus pain (pain with external rotation).

Patients were excluded if their history included prior subacromial CSI, adhesive capsulitis (inability to passively abduct shoulder to 90° with scapular stabilization), calcific tendonitis, radiographic evidence of os acromiale, cervical radiculopathy, Spurling sign, neck pain, radiating arm pain or numbness, sensory deficits, or neck and upper extremity motor dysfunction. Also excluded were patients with full-thickness rotator cuff tear, weakness on arm elevation, positive "drop arm sign," or high-riding humerus on standing shoulder radiograph. Patients who had work-related injuries or who were involved in worker compensation were excluded as well.

Enrolled patients were randomly assigned (with use of a computer-based random number generator) to receive either anterior CSI or posterior CSI.

Injection Procedures

All patients were administered 5 mL of lidocaine 1% (without epinephrine) and 2 mL (80 mg) of triamcinolone by 2 board-certified orthopedic surgeons using a 22-gauge 1½-inch needle. For patients who received their subacromial CSI by the anterior route, the arm was held in 0° of abduction and 20° of external rotation. The needle was inserted medial to the humeral head, lateral to the coracoid process, beginning 1 cm inferior to the clavicle with the needle directed posteriorly and laterally toward the acromion.¹⁰ For patients who received their CSI by the posterior route, the arm was held in 0° of abduction, the posterolateral corner of the acromion was identified by palpation, and the needle was inserted 1 cm inferior and medial to this point with the needle directed anteriorly and laterally toward the acromion.^10,12 In both groups, the subacromial space was identified when a drop in pressure was felt during needle insertion. Accuracy was assessed post hoc by asking patients to grade their response to the injection on a visual analog scale (VAS); VAS score was used as a surrogate for improvement. All patients had a positive Neer test: Pain decreased with impingement maneuvers immediately after injection.

All patients were referred for PT provided according to an evidence-based rehabilitation protocol.¹⁴ This program emphasized range of motion with shoulder shrugs, scapular retraction, and pendulum exercises; flexibility with stretching exercises targeting the anterior and posterior aspects of the shoulder and cane stretching for forward elevation and external rotation; and strength with strengthening exercises involving the rotator cuff and scapular stabilizers.

Outcome Measures

Pain was measured with VAS scores and function with Single Assessment Numeric Evaluation (SANE) scores. The VAS is a validated outcome measure of pain intensity. A numeric version of the VAS was used: Patients selected the whole number, from 0 (no pain) to 10 (worst possible pain), that best reflected their pain intensity. On SANE, another validated outcome measure, patients rated their shoulder function as a percentage of normal, from 0% (no function possible) to 100% (perfect).¹⁵ Before injection, all patients were administered the VAS and SANE questionnaires to establish their baseline pain level and opinion of shoulder function. These measures were repeated 1, 3, and 6 months after injection. Telephone interviews were conducted at 1 month and 6 months. Patients were asked to return to clinic 3 months after injection as part of the standard of care. At 3 months, 47 (86%) of the 55 patients returned for follow-up and were administered the VAS and SANE questionnaires; the other 8 completed the questionnaires by telephone. At each time point, patients were asked to report on their participation in PT and/or adherence to their home exercise program.

Statistical Analysis

Power analysis performed with Student t test and a 2-sided level of P = .05 compared VAS pain scores between the anterior and posterior injection routes and found a mean (SD) difference of 1.4 (1.7).¹⁶ Power calculations made with nQuery Advisor Version 7.0 (Statistical Solutions) indicated a total sample size of 60 patients (30/group) would provide 80% power for detecting a significant difference assuming a 20% dropout rate.

Two-way mixed-model analysis of variance (ANOVA) was used to compare the anterior and posterior routes for statistical differences in both VAS pain scores and SANE function scores at baseline and 1, 3, and 6 months after injection. Likewise, time at baseline (just before injection)was compared with follow-up (1, 3, 6 months) with 2-way mixed-model ANOVA adjusting for anterior or posterior route. Multivariate analysis was performed to evaluate differences between baseline and 6-month follow-up with respect to anterior and posterior injection routes, controlling for age, sex, and body mass index (BMI) for VAS and SANE scores. Parametric testing methods were used for statistical analysis, which was performed with IBM SPSS Statistics Version 21.0 (IBM Corp). Significance was set at P < .05.

Results

Patient Characteristics

Of the 55 patients enrolled, 25 (46%) received anterior subacromial CSI and 30 (54%) received posterior CSI. All enrolled patients had a positive Neer impingement test immediately after injection. Mean (SD) age was 48 (9.3) years for anterior group patients and 48 (9.0) years for posterior group patients. There was no significant difference in age or BMI between the 2 groups (Table).

Five patients (9%) were excluded from the study after randomization and CSI: 2 for a full-thickness rotator cuff tear, 1 for a Bankart lesion, 1 for adhesive capsulitis, and 1 for a worker compensation claim.

One month after injection, 41 patients (75%) reported having engaged in PT as prescribed. Of the 47 patients (86%) who returned for the 3-month follow-up, 25 (46%) reported having engaged in PT between 1 month and 3 months after injection. Fourteen patients (26%) reported attending PT between 3 and 6 months post-injection.

Outcome Measures

Two-way repeated-measures ANOVA with age, sex, and BMI included as covariates revealed no significant differences in VAS scores between the anterior and posterior groups at any time point (P = .45). Both groups had highly significant pain reductions (anterior, F = 9.71, P < .001; posterior, F = 13.46, P < .001). Figure 1 shows mean VAS scores and significant reductions in pain 1, 3, and 6 months after injection (see asterisks for anterior and posterior groups; P < .001 for all). The groups had parallel rates of pain reduction over time, as indicated by a nonsignificant (P = .50) difference in slopes. These pain score reductions were significant for both injection routes and were independent of age, sex, and BMI (P > .05 for all).

Two-way repeated-measures ANOVA with age, sex, and BMI included as covariates revealed no significant differences in SANE scores between the anterior and posterior groups, except for a higher mean score in the anterior group at 3 months
(P = .02). There were no other group differences (P > .10 for all). Both groups had highly significant improvements in function (anterior, F = 17.34,
P < .001; posterior, F = 13.57, P < .001). Figure 2 shows mean SANE scores and significant improvement at 1, 3, and 6 months (see asterisks for anterior and posterior groups; P < .001 for all). The groups had parallel rates of improved function over time, as indicated by a nonsignificant (P = .51) difference in slopes. These function score improvements were significant for both injection routes and were independent of age, sex, and BMI (P > .05 for all).

From the results of this prospective randomized study, we concluded subacromial CSI significantly reduces pain and improves function regardless of route used. In addition, age, sex, and BMI do not significantly affect the efficacy of either anterior CSI or posterior CSI.

Discussion

In patients with SIS, anterior CSI and posterior CSI provided significant improvements in pain and function 1, 3, and 6 months after injection. These effects were independent of age, sex, BMI, and PT participation. There were no significant differences in outcomes between injection routes.

When conservative treatments for SIS do not resolve symptoms, inflammation and pain can be reduced with use of subacromial CSI.^4-8 Although clinical outcomes are inconsistent, CSI can be used to address SIS symptoms in appropriate patients. Specifically, Blair and colleagues⁶ found that, CSI consisting of 4 mL of lidocaine 1% (without epinephrine) and 2 mL (80 mg) of triamcinolone was effective in alleviating shoulder pain and improving shoulder range of motion. Other authors have similarly reported improved outcomes after subacromial injection and short-term follow-up with PT.^4,7,8 Our findings are consistent with these reports: CSI coupled with a structured rehabilitation program is effective in alleviating symptoms associated with acute or subacute SIS.

Numerous studies have found improved clinical outcomes after anterior CSI and after posterior CSI,^6-8 but no study has directly compared the clinical impact of anterior CSI with that of posterior CSI—which suggests injection route may not affect ultimate clinical outcomes.

CSI accuracy has been studied extensively.^10-12,17-20 Although 2 studies found similar accuracy for anterior and posterior routes,^10,11 there may be a sex difference: In women, a posterior route may be less accurate than an anterior or a lateral route.¹² Collectively, these studies expose the inherent difficulty in treating shoulder pain with localized subacromial injection. Therapy may fail because of errant needle positioning. Two prospective studies found improved clinical outcomes with successful delivery of medication into the subacromial space.^17,18 Poor clinical outcomes may result from inaccurate CSI.

In contrast to other clinical studies, our study found that injection route was not associated with differences in clinical response. In a prospective randomized clinical trial in which 75 patients received a subacromial injection, Marder and colleagues¹² found anterior routes 84% accurate and posterior routes 56% accurate; they concluded acromion anatomy and subacromial bursa anatomy make posterior injections more difficult. As theorized by Gruson and colleagues,¹³ with use of an anterior route, the needle enters inferior to the concavity of the acromion and provides easier access to the subacromial space. This idea is in line with Marder and colleagues’¹² conclusion that subacromial bursa anatomy provides a favorable environment for accurate CSI.

If accuracy is positively correlated with clinical improvement and anterior routes are more accurate, there should be a difference in response to posterior injections. Our results provide evidence that clinical response to CSI may not depend on injection accuracy. Perhaps merely placing the corticosteroid near the bursa is adequate for improving symptoms or perhaps some of the clinical improvement is due to the systemic effect of corticosteroids. These possibilities require further analysis.

Establishing the efficacy of CSI in SIS is difficult. The literature includes various study designs, different CSI indications and medication formulations, and varying emphasis on the role of organized PT. Rehabilitation has been found to alleviate joint pain by reducing inflammation,¹⁴ but data do not universally support this finding.^21,22 Nevertheless, use of PT might explain the divergence in clinical outcomes reported by Marder and colleagues,¹² who found anterior CSI more accurate than posterior CSI. In our practice, PT is recommended for all SIS patients, not only those who have CSI. Thus, our findings are framed within the context of successful CSI but may include patients who improved with PT alone. This issue raises the question of whether subacromial CSI should be guided by ultrasound. Ultrasound guidance can improve CSI accuracy and clinical outcomes,^23-25 though the value of this benefit is debated.²⁶

This study had several limitations. First, pain relief was patient reported. Second, the treatment plan involved CSI with PT but did not control for CSI used alone. PT, which is part of the standard of care for patients with SIS, added another degree of complexity to the study. Third, there may have been some variability in SIS severity (stage 1, 2, or 3). Fourth, although the study design controlled for various shoulder pathologies, advanced imaging, which could have provided diagnosis confirmation, was not available for all patients. Therefore, concurrent conditions may have confounded results. However, randomization was used to try to minimize this effect. Fifth, although injection routes were randomly assigned, the trial was not blinded. Sixth, the study was underpowered by 1 patient, as there was an estimated 20% dropout rate over 3 and 6 months of follow-up. However, we do not think our results were significantly affected.

Although more research is needed to fully describe the role of subacromial CSI in SIS, our study findings suggested that CSI using either an anterior or a posterior route creates a window of symptomatic relief in which patients may be able to engage in PT.

Conclusion

Both anterior CSI and posterior CSI significantly improved pain and function for up to 6 months. No differences were found between anterior and posterior CSIs. In the context of this study, CSI combined with structured PT produced significant improvement in pain and function in patients with SIS, regardless of injection route used. Clinicians should rely on their clinical acumen when selecting injection routes, as anterior and posterior are both beneficial.

Take-Home Points

• When conservative treatments for SIS do not resolve symptoms, inflammation and pain can be reduced with use of subacromial CSI.

• Both anterior CSI and posterior CSI significantly improved pain and function for up to 6 months

• CSI combined with structured PT produced significant improvement in pain and function in patients with SIS, regardless of injection route used.

• Clinical response to CSI may not depend on injection accuracy.

• Clinicians should rely on their clinical acumen when selecting injection routes, as anterior and posterior are both beneficial.

Shoulder pain, a common clinical problem, occurs in 7% to 34% of the general population and in 21% of people older than 70 years.¹Subacromial impingement refers to shoulder pain resulting from mechanical impingement of the rotator cuff underneath the coracoacromial arch between the acromion and the humeral head.^2,3 Subacromial impingement syndrome (SIS) is the most common cause of shoulder pain, resulting in significant functional deficits and disability.³

Treatment options for SIS include conservative modalities such as use of nonsteroidal anti-inflammatory drugs, physical therapy (PT), and subacromial corticosteroid injections (CSIs). Studies have found short- and long-term improvement in pain, function, and range of motion after CSI.^4-8 Subacromial CSI can be administered through an anterior or a posterior route.^4,9 There have been several studies of the accuracy of anterior and posterior CSIs,^10-12 with 2 studies finding similar accuracy for these routes.^10,11 However, there may be a sex difference: In women, a posterior route may be less accurate than an anterior or a lateral route.¹²

Although the accuracy of anterior and posterior routes has been studied, their effect on clinical outcomes has not. We conducted a study to understand the effects of anterior and posterior CSIs on SIS. As one of the accuracy studies suggested anterior CSI is more accurate—the anterior route was theorized to provide easier access to the subacromial space¹²—we hypothesized patients treated with anterior CSI would have superior clinical outcomes 6 months after injection.^12,13

Materials and Methods

Study Participants and Randomization

After this study received Institutional Review Board approval, patients with shoulder pain of more than 3 months’ duration and consistent with SIS were screened for inclusion. Eligible patients had pain in the anterior biceps and over the top of the shoulder with overhead activities as well as one or more clinical findings on physical examination: Hawkins-Kennedy sign, Neer sign, painful arc, and infraspinatus pain (pain with external rotation).

Patients were excluded if their history included prior subacromial CSI, adhesive capsulitis (inability to passively abduct shoulder to 90° with scapular stabilization), calcific tendonitis, radiographic evidence of os acromiale, cervical radiculopathy, Spurling sign, neck pain, radiating arm pain or numbness, sensory deficits, or neck and upper extremity motor dysfunction. Also excluded were patients with full-thickness rotator cuff tear, weakness on arm elevation, positive "drop arm sign," or high-riding humerus on standing shoulder radiograph. Patients who had work-related injuries or who were involved in worker compensation were excluded as well.

Enrolled patients were randomly assigned (with use of a computer-based random number generator) to receive either anterior CSI or posterior CSI.

Injection Procedures

All patients were administered 5 mL of lidocaine 1% (without epinephrine) and 2 mL (80 mg) of triamcinolone by 2 board-certified orthopedic surgeons using a 22-gauge 1½-inch needle. For patients who received their subacromial CSI by the anterior route, the arm was held in 0° of abduction and 20° of external rotation. The needle was inserted medial to the humeral head, lateral to the coracoid process, beginning 1 cm inferior to the clavicle with the needle directed posteriorly and laterally toward the acromion.¹⁰ For patients who received their CSI by the posterior route, the arm was held in 0° of abduction, the posterolateral corner of the acromion was identified by palpation, and the needle was inserted 1 cm inferior and medial to this point with the needle directed anteriorly and laterally toward the acromion.^10,12 In both groups, the subacromial space was identified when a drop in pressure was felt during needle insertion. Accuracy was assessed post hoc by asking patients to grade their response to the injection on a visual analog scale (VAS); VAS score was used as a surrogate for improvement. All patients had a positive Neer test: Pain decreased with impingement maneuvers immediately after injection.

All patients were referred for PT provided according to an evidence-based rehabilitation protocol.¹⁴ This program emphasized range of motion with shoulder shrugs, scapular retraction, and pendulum exercises; flexibility with stretching exercises targeting the anterior and posterior aspects of the shoulder and cane stretching for forward elevation and external rotation; and strength with strengthening exercises involving the rotator cuff and scapular stabilizers.

Outcome Measures

Pain was measured with VAS scores and function with Single Assessment Numeric Evaluation (SANE) scores. The VAS is a validated outcome measure of pain intensity. A numeric version of the VAS was used: Patients selected the whole number, from 0 (no pain) to 10 (worst possible pain), that best reflected their pain intensity. On SANE, another validated outcome measure, patients rated their shoulder function as a percentage of normal, from 0% (no function possible) to 100% (perfect).¹⁵ Before injection, all patients were administered the VAS and SANE questionnaires to establish their baseline pain level and opinion of shoulder function. These measures were repeated 1, 3, and 6 months after injection. Telephone interviews were conducted at 1 month and 6 months. Patients were asked to return to clinic 3 months after injection as part of the standard of care. At 3 months, 47 (86%) of the 55 patients returned for follow-up and were administered the VAS and SANE questionnaires; the other 8 completed the questionnaires by telephone. At each time point, patients were asked to report on their participation in PT and/or adherence to their home exercise program.

Statistical Analysis

Power analysis performed with Student t test and a 2-sided level of P = .05 compared VAS pain scores between the anterior and posterior injection routes and found a mean (SD) difference of 1.4 (1.7).¹⁶ Power calculations made with nQuery Advisor Version 7.0 (Statistical Solutions) indicated a total sample size of 60 patients (30/group) would provide 80% power for detecting a significant difference assuming a 20% dropout rate.

Two-way mixed-model analysis of variance (ANOVA) was used to compare the anterior and posterior routes for statistical differences in both VAS pain scores and SANE function scores at baseline and 1, 3, and 6 months after injection. Likewise, time at baseline (just before injection)was compared with follow-up (1, 3, 6 months) with 2-way mixed-model ANOVA adjusting for anterior or posterior route. Multivariate analysis was performed to evaluate differences between baseline and 6-month follow-up with respect to anterior and posterior injection routes, controlling for age, sex, and body mass index (BMI) for VAS and SANE scores. Parametric testing methods were used for statistical analysis, which was performed with IBM SPSS Statistics Version 21.0 (IBM Corp). Significance was set at P < .05.

Results

Patient Characteristics

Of the 55 patients enrolled, 25 (46%) received anterior subacromial CSI and 30 (54%) received posterior CSI. All enrolled patients had a positive Neer impingement test immediately after injection. Mean (SD) age was 48 (9.3) years for anterior group patients and 48 (9.0) years for posterior group patients. There was no significant difference in age or BMI between the 2 groups (Table).

Five patients (9%) were excluded from the study after randomization and CSI: 2 for a full-thickness rotator cuff tear, 1 for a Bankart lesion, 1 for adhesive capsulitis, and 1 for a worker compensation claim.

One month after injection, 41 patients (75%) reported having engaged in PT as prescribed. Of the 47 patients (86%) who returned for the 3-month follow-up, 25 (46%) reported having engaged in PT between 1 month and 3 months after injection. Fourteen patients (26%) reported attending PT between 3 and 6 months post-injection.

Outcome Measures

Two-way repeated-measures ANOVA with age, sex, and BMI included as covariates revealed no significant differences in VAS scores between the anterior and posterior groups at any time point (P = .45). Both groups had highly significant pain reductions (anterior, F = 9.71, P < .001; posterior, F = 13.46, P < .001). Figure 1 shows mean VAS scores and significant reductions in pain 1, 3, and 6 months after injection (see asterisks for anterior and posterior groups; P < .001 for all). The groups had parallel rates of pain reduction over time, as indicated by a nonsignificant (P = .50) difference in slopes. These pain score reductions were significant for both injection routes and were independent of age, sex, and BMI (P > .05 for all).

Two-way repeated-measures ANOVA with age, sex, and BMI included as covariates revealed no significant differences in SANE scores between the anterior and posterior groups, except for a higher mean score in the anterior group at 3 months
(P = .02). There were no other group differences (P > .10 for all). Both groups had highly significant improvements in function (anterior, F = 17.34,
P < .001; posterior, F = 13.57, P < .001). Figure 2 shows mean SANE scores and significant improvement at 1, 3, and 6 months (see asterisks for anterior and posterior groups; P < .001 for all). The groups had parallel rates of improved function over time, as indicated by a nonsignificant (P = .51) difference in slopes. These function score improvements were significant for both injection routes and were independent of age, sex, and BMI (P > .05 for all).

From the results of this prospective randomized study, we concluded subacromial CSI significantly reduces pain and improves function regardless of route used. In addition, age, sex, and BMI do not significantly affect the efficacy of either anterior CSI or posterior CSI.

Discussion

In patients with SIS, anterior CSI and posterior CSI provided significant improvements in pain and function 1, 3, and 6 months after injection. These effects were independent of age, sex, BMI, and PT participation. There were no significant differences in outcomes between injection routes.

When conservative treatments for SIS do not resolve symptoms, inflammation and pain can be reduced with use of subacromial CSI.^4-8 Although clinical outcomes are inconsistent, CSI can be used to address SIS symptoms in appropriate patients. Specifically, Blair and colleagues⁶ found that, CSI consisting of 4 mL of lidocaine 1% (without epinephrine) and 2 mL (80 mg) of triamcinolone was effective in alleviating shoulder pain and improving shoulder range of motion. Other authors have similarly reported improved outcomes after subacromial injection and short-term follow-up with PT.^4,7,8 Our findings are consistent with these reports: CSI coupled with a structured rehabilitation program is effective in alleviating symptoms associated with acute or subacute SIS.

Numerous studies have found improved clinical outcomes after anterior CSI and after posterior CSI,^6-8 but no study has directly compared the clinical impact of anterior CSI with that of posterior CSI—which suggests injection route may not affect ultimate clinical outcomes.

CSI accuracy has been studied extensively.^10-12,17-20 Although 2 studies found similar accuracy for anterior and posterior routes,^10,11 there may be a sex difference: In women, a posterior route may be less accurate than an anterior or a lateral route.¹² Collectively, these studies expose the inherent difficulty in treating shoulder pain with localized subacromial injection. Therapy may fail because of errant needle positioning. Two prospective studies found improved clinical outcomes with successful delivery of medication into the subacromial space.^17,18 Poor clinical outcomes may result from inaccurate CSI.

In contrast to other clinical studies, our study found that injection route was not associated with differences in clinical response. In a prospective randomized clinical trial in which 75 patients received a subacromial injection, Marder and colleagues¹² found anterior routes 84% accurate and posterior routes 56% accurate; they concluded acromion anatomy and subacromial bursa anatomy make posterior injections more difficult. As theorized by Gruson and colleagues,¹³ with use of an anterior route, the needle enters inferior to the concavity of the acromion and provides easier access to the subacromial space. This idea is in line with Marder and colleagues’¹² conclusion that subacromial bursa anatomy provides a favorable environment for accurate CSI.

If accuracy is positively correlated with clinical improvement and anterior routes are more accurate, there should be a difference in response to posterior injections. Our results provide evidence that clinical response to CSI may not depend on injection accuracy. Perhaps merely placing the corticosteroid near the bursa is adequate for improving symptoms or perhaps some of the clinical improvement is due to the systemic effect of corticosteroids. These possibilities require further analysis.

Establishing the efficacy of CSI in SIS is difficult. The literature includes various study designs, different CSI indications and medication formulations, and varying emphasis on the role of organized PT. Rehabilitation has been found to alleviate joint pain by reducing inflammation,¹⁴ but data do not universally support this finding.^21,22 Nevertheless, use of PT might explain the divergence in clinical outcomes reported by Marder and colleagues,¹² who found anterior CSI more accurate than posterior CSI. In our practice, PT is recommended for all SIS patients, not only those who have CSI. Thus, our findings are framed within the context of successful CSI but may include patients who improved with PT alone. This issue raises the question of whether subacromial CSI should be guided by ultrasound. Ultrasound guidance can improve CSI accuracy and clinical outcomes,^23-25 though the value of this benefit is debated.²⁶

This study had several limitations. First, pain relief was patient reported. Second, the treatment plan involved CSI with PT but did not control for CSI used alone. PT, which is part of the standard of care for patients with SIS, added another degree of complexity to the study. Third, there may have been some variability in SIS severity (stage 1, 2, or 3). Fourth, although the study design controlled for various shoulder pathologies, advanced imaging, which could have provided diagnosis confirmation, was not available for all patients. Therefore, concurrent conditions may have confounded results. However, randomization was used to try to minimize this effect. Fifth, although injection routes were randomly assigned, the trial was not blinded. Sixth, the study was underpowered by 1 patient, as there was an estimated 20% dropout rate over 3 and 6 months of follow-up. However, we do not think our results were significantly affected.

Although more research is needed to fully describe the role of subacromial CSI in SIS, our study findings suggested that CSI using either an anterior or a posterior route creates a window of symptomatic relief in which patients may be able to engage in PT.

Conclusion

Both anterior CSI and posterior CSI significantly improved pain and function for up to 6 months. No differences were found between anterior and posterior CSIs. In the context of this study, CSI combined with structured PT produced significant improvement in pain and function in patients with SIS, regardless of injection route used. Clinicians should rely on their clinical acumen when selecting injection routes, as anterior and posterior are both beneficial.

NASHVILLE, TENN. – At the University of North Carolina at Chapel Hill, many infants who would previously have been transferred to the NICU for asymptomatic hypoglycemia now are staying with their moms, thanks to a new protocol that holds off on blood glucose testing until infants are fed for the first time and glucose homeostasis can begin.

Not too long ago, the university realized it had a problem that’s probably familiar to other institutions: Its system to monitor newborns at risk for hypoglycemia – those born to diabetic mothers, or who are small or large for gestational age – put too many infants with asymptomatic hypoglycemia into the NICU when they didn’t really need to be there.

Nurse practitioners “were tired of transferring babies they felt were responsive to feeding and did not actually require NICU care,” and “a growing number of families were unhappy with being separated from infants that were well-appearing and feeding well at a time when moms were trying to establish breast feeding and bonding. There was frustration with our protocol,” which “seemed rigid and outdated,” said Ashley Sutton, MD, a pediatric hospitalist at the university.

[email protected]

NASHVILLE, TENN. – At the University of North Carolina at Chapel Hill, many infants who would previously have been transferred to the NICU for asymptomatic hypoglycemia now are staying with their moms, thanks to a new protocol that holds off on blood glucose testing until infants are fed for the first time and glucose homeostasis can begin.

Not too long ago, the university realized it had a problem that’s probably familiar to other institutions: Its system to monitor newborns at risk for hypoglycemia – those born to diabetic mothers, or who are small or large for gestational age – put too many infants with asymptomatic hypoglycemia into the NICU when they didn’t really need to be there.

Nurse practitioners “were tired of transferring babies they felt were responsive to feeding and did not actually require NICU care,” and “a growing number of families were unhappy with being separated from infants that were well-appearing and feeding well at a time when moms were trying to establish breast feeding and bonding. There was frustration with our protocol,” which “seemed rigid and outdated,” said Ashley Sutton, MD, a pediatric hospitalist at the university.

[email protected]

NASHVILLE, TENN. – At the University of North Carolina at Chapel Hill, many infants who would previously have been transferred to the NICU for asymptomatic hypoglycemia now are staying with their moms, thanks to a new protocol that holds off on blood glucose testing until infants are fed for the first time and glucose homeostasis can begin.

Not too long ago, the university realized it had a problem that’s probably familiar to other institutions: Its system to monitor newborns at risk for hypoglycemia – those born to diabetic mothers, or who are small or large for gestational age – put too many infants with asymptomatic hypoglycemia into the NICU when they didn’t really need to be there.

Nurse practitioners “were tired of transferring babies they felt were responsive to feeding and did not actually require NICU care,” and “a growing number of families were unhappy with being separated from infants that were well-appearing and feeding well at a time when moms were trying to establish breast feeding and bonding. There was frustration with our protocol,” which “seemed rigid and outdated,” said Ashley Sutton, MD, a pediatric hospitalist at the university.

[email protected]

The mobile companion app (Apple products only) for VESAP4 is expected to be released by mid-September. The app permits users to access the program offline anywhere and sync up with the desktop app when later connected to the Internet.

It will be available on the iTunes store and is free to VESAP4 purchasers. Learn more about the fourth edition of the Vascular Education and Self-Assessment Program (VESAP4) here.

The mobile companion app (Apple products only) for VESAP4 is expected to be released by mid-September. The app permits users to access the program offline anywhere and sync up with the desktop app when later connected to the Internet.

It will be available on the iTunes store and is free to VESAP4 purchasers. Learn more about the fourth edition of the Vascular Education and Self-Assessment Program (VESAP4) here.

The mobile companion app (Apple products only) for VESAP4 is expected to be released by mid-September. The app permits users to access the program offline anywhere and sync up with the desktop app when later connected to the Internet.

It will be available on the iTunes store and is free to VESAP4 purchasers. Learn more about the fourth edition of the Vascular Education and Self-Assessment Program (VESAP4) here.

SVS is seeking proposals for invited sessions from internal committees and members alike for the 2018 Vascular Annual Meeting, June 20-23 (exhibits: June 21 to 22; plenaries: June 21 to 23) in Boston, Mass.

Invited sessions consist of postgraduate courses, breakfast sessions, concurrent sessions and workshops/small-group sessions. Submitters will be asked to address educational needs, provide objectives, indicate proposed formats and identify target audiences.

The deadline is 3 p.m. Central Daylight Time, Friday, Sept. 15. Submitters will be notified the week of Sept. 25 if their proposals have been selected for further development. Contact [email protected] or call 312-334-2327 with questions.

SVS is seeking proposals for invited sessions from internal committees and members alike for the 2018 Vascular Annual Meeting, June 20-23 (exhibits: June 21 to 22; plenaries: June 21 to 23) in Boston, Mass.

Invited sessions consist of postgraduate courses, breakfast sessions, concurrent sessions and workshops/small-group sessions. Submitters will be asked to address educational needs, provide objectives, indicate proposed formats and identify target audiences.

The deadline is 3 p.m. Central Daylight Time, Friday, Sept. 15. Submitters will be notified the week of Sept. 25 if their proposals have been selected for further development. Contact [email protected] or call 312-334-2327 with questions.

SVS is seeking proposals for invited sessions from internal committees and members alike for the 2018 Vascular Annual Meeting, June 20-23 (exhibits: June 21 to 22; plenaries: June 21 to 23) in Boston, Mass.

Invited sessions consist of postgraduate courses, breakfast sessions, concurrent sessions and workshops/small-group sessions. Submitters will be asked to address educational needs, provide objectives, indicate proposed formats and identify target audiences.

The deadline is 3 p.m. Central Daylight Time, Friday, Sept. 15. Submitters will be notified the week of Sept. 25 if their proposals have been selected for further development. Contact [email protected] or call 312-334-2327 with questions.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.

Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.

The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).

The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.

In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.

Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.

Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.

With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.

Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.

“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”

They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.

In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.

Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.

In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.

Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.

“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.

“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”

Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.

Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.

The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).

The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.

In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.

Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.

Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.

With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.

Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.

“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”

They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.

In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.

Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.

In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.

Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.

“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.

“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”

Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.

Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.

The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).

The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.

About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.

In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.

Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.

Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.

With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.

Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.

“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”

They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.

In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.

Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.

In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.

Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.

“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.

“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”

Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.

Statin Prescription Varies in Stroke Belt

Less than half of patients with stroke discharged from the hospital receive a prescription for statins, and the likelihood of a prescription varies by patients’ location, sex, age, and race, according to a study published August 2 in the Journal of the American Heart Association. Researchers analyzed discharge medications for 323 participants hospitalized for an ischemic stroke during follow-up of the Reasons for Geographic and Racial Differences in Stroke study. In the Stroke Belt, participants ages 65 and older were 47% less likely to be discharged on a statin, compared with people younger than 65. Compared with women, men in the Stroke Belt were 31% less likely to be discharged on a statin, while men outside the Stroke Belt were more likely to be discharged on a statin.

Albright KC, Howard VJ, Howard G, et al. Age and sex disparities in discharge statin prescribing in the stroke belt: evidence from the Reasons for Geographic and Racial Differences in Stroke Study. J Am Heart Assoc. 2017;6(8).

Midlife Vascular Risk Factors Increase Risk of Dementia

Midlife vascular risk factors are associated with increased risk of dementia in blacks and whites, according to a study published online ahead of print August 7 in JAMA Neurology. In the Atherosclerosis Risk in Communities study, investigators measured demographic and vascular risk factors at baseline (ie, obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia), along with the presence of the APOE ε4 genotype. After the baseline visit, participants had four additional in-person visits. In all, 1,516 cases of dementia (57.0% female and 34.9% black, with a mean age at visit 1 of 57.4) were identified among 15,744 participants. Black race, older age, lower educational attainment, and APOE ε4 genotype were associated with increased risk of dementia, as were midlife smoking, diabetes, prehypertension, and hypertension.

Gottesman RF, Albert MS, Alonso A, et al. Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort. JAMA Neurol. 2017 August 7 [Epub ahead of print].

Resistance Training May Slow the Progression of MS

Progressive resistance training may have a neuroprotective or neuroregenerative effect in relapsing-remitting multiple sclerosis (MS), according to a study published online ahead of print July 1 in Multiple Sclerosis Journal. This study was a 24-week randomized controlled crossover trial. Participants were assigned to training or to a wait list. Assessments included disability measures and MRI. The MS Functional Composite score improved in the training group, but disability, lesion load, and global brain volumes did not differ between groups. The researchers noted higher absolute cortical thickness values in 19 of 74 investigated cortical regions after progressive resistance training. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups in the anterior cingulate gyrus, temporal pole, orbital sulcus, and inferior temporal sulcus.

Kjølhede T, Siemonsen S, Wenzel D, et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult Scler. 2017 Jul 1 [Epub ahead of print].

Noninvasive Device Measures Intracranial Pressure

A noninvasive device measures intracranial pressure (ICP) accurately, according to research published online ahead of print August 8 in the Journal of Neurosurgery. In patients with traumatic brain injury and subarachnoid hemorrhage who were undergoing treatment in a neurocritical intensive care unit, researchers recorded ICP using the gold-standard method of invasive external ventricular drainage or intraparenchymal monitoring. In addition, the authors simultaneously measured ICP noninvasively with a device that uses advanced signal-analysis algorithms for acoustic signals propagating through the cranium. Data were collected in 14 patients, yielding 2,543 data points of continuous parallel ICP values. For measurements at the ≥ 17-mm Hg cutoff, the sensitivity and specificity of the noninvasive device were 0.7541 and 0.8887, respectively. ICP values obtained using noninvasive and invasive monitoring methods correlated well.

Ganslandt O, Mourtzoukos S, Stadlbauer A, et al. Evaluation of a novel noninvasive ICP monitoring device in patients undergoing invasive ICP monitoring: preliminary results. J Neurosurg. 2017 Aug 8 [Epub ahead of print].

Strokes Decline Among Men, But Not Women

The rate of stroke in the US has declined among men, but not among women, according to a study published online ahead of print August 9 in Neurology. Researchers collected data on 1.3 million adults in Ohio and Kentucky between 1993 and 2010. They used medical records to identify first-ever strokes during four one-year periods. The researchers observed 7,710 incident strokes in the four periods, and 57% of them were among women. The incidence of all strokes decreased over time in men (263 to 192), but not in women (217 to 198). The researchers found a similar sex difference in the change in the rate of ischemic stroke (ie, a decline from 238 to 165 among men, and a change from 193 to 173 among women).

Madsen TE, Khoury J, Alwell K, et al. Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study. Neurology. 2017 Aug 9 [Epub ahead of print].

Link Between Alcohol Intake and Cognitively Healthy Longevity

Older adults who consume alcohol moderately on a regular basis are more likely to live to age 85 without dementia or other cognitive impairments than nondrinkers, according to a study published in the August issue of the Journal of Alzheimer’s Disease. Researchers examined 1,344 older community-dwelling adults and assessed alcohol intake by questionnaire in 1984–1987. They evaluated cognitive function in approximately four-year intervals between 1988 and 2009. About 49% of participants reported moderate alcohol intake, and 48% reported drinking almost daily. Relative to nondrinkers, moderate and heavy drinkers had significantly higher adjusted odds of survival to age 85 without cognitive impairment. Near-daily drinkers had two- to threefold higher adjusted odds of cognitively healthy longevity versus living to at least age 85 with cognitive impairment or death before age 85.

Richard EL, Kritz-Silverstein D, Laughlin GA, et al. Alcohol intake and cognitively healthy longevity in community-dwelling adults: The Rancho Bernardo Study. J Alzheimers Dis. 2017;59(3):803-814.

MRI Shows Brain Differences in Genetic Autism

In two genetically related cohorts at high risk for autism, reciprocal neuroanatomic abnormalities were associated with cognitive and behavioral impairments, according to a study published online ahead of print August 8 in Radiology. Researchers performed MRI on 79 carriers of a deletion at 16p11.2, 79 carriers of a duplication at 16p11.2, 64 unaffected family members, and 109 controls. The participants completed cognitive and behavioral tests, and neuroradiologists reviewed the images for development-related abnormalities. The researchers found differences in the brain structures of deletion and duplication carriers, compared with noncarriers. Deletion carriers had brain overgrowth, and duplication carriers had brain undergrowth. When investigators compared cognitive assessments to imaging findings, they found that any imaging feature associated with the deletion carriers indicated worse daily living, communication, and social skills.

Owen JP, Bukshpun P, Pojman N, et al. Brain MR imaging findings and associated outcomes in carriers of the reciprocal copy number variation at 16p11.2. Radiology. 2017 Aug 8 [Epub ahead of print].

FDA Clears Stimpod NMS460 for Relief of Chronic Pain

The FDA has cleared Stimpod NMS460, a noninvasive neuromodulation device, for the symptomatic relief and management of chronic intractable pain. The unit also can be used for the adjunctive treatment of postsurgical pain, posttraumatic acute pain, and pain control due to rehabilitation. The device has a pulsed radio frequency waveform that creates electromagnetic effects similar to those of invasive pulsed radio frequency treatments. Treatment is applied transcutaneously. Case studies have shown quick and notable relief of chronic intractable pain. The treatment has no known side effects. The Stimpod NMS460 also incorporates nerve-locating technology that includes a nerve-mapping probe that enables practitioners to evaluate the treatment progress of damaged nerves. Xavant Technology, which markets Stimpod NMS460, is headquartered in Pretoria, South Africa.

Longer Sleep Is Associated With Lower BMI

Adults who have poor sleep patterns are more likely to be overweight or obese and have poorer metabolic health, according to a study published July 27 in PLoS One. Researchers analyzed associations between sleep duration and adiposity, selected metabolic health markers, and diet using National Diet and Nutrition Survey data. In all, 1,615 adults (57.1% female) between ages 19 and 65 completed questions about sleep duration and three to four days of food diaries. Investigators recorded blood pressure and waist circumference. Fasting blood lipids, glucose, glycated hemoglobin, thyroid hormones, and high-sensitivity C-reactive protein were measured in a subset of participants. After adjusting for age, ethnicity, sex, smoking, and socioeconomic status, sleep duration was negatively associated with BMI and waist circumference. Sleep duration was positively associated with high-density lipoprotein cholesterol.

Potter GDM, Cade JE, Hardie LJ. Longer sleep is associated with lower BMI and favorable metabolic profiles in UK adults: findings from the National Diet and Nutrition Survey. PLoS One. 2017; 12(7):e0182195.

Can Bleeding Risk After Stroke Be Predicted?

The S2TOP-BLEED score can estimate three-year major bleeding risk in patients with transient ischemic attack (TIA) or ischemic stroke who use antiplatelet agents, according to a study published online ahead of print August 2 in Neurology. To develop this prediction model, researchers combined data from six trials investigating antiplatelet therapy after TIA or ischemic stroke. They performed Cox regression analyses stratified by trial to study the association between predictors and major bleeding. Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed three-year risk of major bleeding was 4.6%. The investigators identified male sex, smoking, type of antiplatelet agents, outcome on modified Rankin Scale ≥ 3, prior stroke, high blood pressure, lower BMI, elderly status, Asian ethnicity, and diabetes as predictors of major bleeding.

Hilkens NA, Algra A, Diener HC, et al. Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets: S2TOP-BLEED. Neurology. 2017 Aug 2 [Epub ahead of print].

Questionnaires Predict Survival in MS

The way patients with multiple sclerosis (MS) answer questionnaires could help to predict their survival rate from the disease, according to a study published July 10 in PLoS Medicine. From July 15, 2004, onward, 2,126 people with MS completed MS Impact Scale-29 (MSIS-29) questionnaires. By 2014, 264 participants had died. Higher baseline MSIS-29 physical score and higher baseline MSIS-29 psychologic score were associated with reduced survival time. In participants with high baseline MSIS-29 scores, mortality risk was greater if the MSIS-29 score worsened over one year. MSIS-29 physical scores were associated with survival time, independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis.

Raffel J, Wallace A, Gveric D, et al. Patient-reported outcomes and survival in multiple sclerosis: a 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29. PLoS Med. 2017;14(7):e1002346.

—Kimberly Williams

Statin Prescription Varies in Stroke Belt

Less than half of patients with stroke discharged from the hospital receive a prescription for statins, and the likelihood of a prescription varies by patients’ location, sex, age, and race, according to a study published August 2 in the Journal of the American Heart Association. Researchers analyzed discharge medications for 323 participants hospitalized for an ischemic stroke during follow-up of the Reasons for Geographic and Racial Differences in Stroke study. In the Stroke Belt, participants ages 65 and older were 47% less likely to be discharged on a statin, compared with people younger than 65. Compared with women, men in the Stroke Belt were 31% less likely to be discharged on a statin, while men outside the Stroke Belt were more likely to be discharged on a statin.

Albright KC, Howard VJ, Howard G, et al. Age and sex disparities in discharge statin prescribing in the stroke belt: evidence from the Reasons for Geographic and Racial Differences in Stroke Study. J Am Heart Assoc. 2017;6(8).

Midlife Vascular Risk Factors Increase Risk of Dementia

Midlife vascular risk factors are associated with increased risk of dementia in blacks and whites, according to a study published online ahead of print August 7 in JAMA Neurology. In the Atherosclerosis Risk in Communities study, investigators measured demographic and vascular risk factors at baseline (ie, obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia), along with the presence of the APOE ε4 genotype. After the baseline visit, participants had four additional in-person visits. In all, 1,516 cases of dementia (57.0% female and 34.9% black, with a mean age at visit 1 of 57.4) were identified among 15,744 participants. Black race, older age, lower educational attainment, and APOE ε4 genotype were associated with increased risk of dementia, as were midlife smoking, diabetes, prehypertension, and hypertension.

Gottesman RF, Albert MS, Alonso A, et al. Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort. JAMA Neurol. 2017 August 7 [Epub ahead of print].

Resistance Training May Slow the Progression of MS

Progressive resistance training may have a neuroprotective or neuroregenerative effect in relapsing-remitting multiple sclerosis (MS), according to a study published online ahead of print July 1 in Multiple Sclerosis Journal. This study was a 24-week randomized controlled crossover trial. Participants were assigned to training or to a wait list. Assessments included disability measures and MRI. The MS Functional Composite score improved in the training group, but disability, lesion load, and global brain volumes did not differ between groups. The researchers noted higher absolute cortical thickness values in 19 of 74 investigated cortical regions after progressive resistance training. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups in the anterior cingulate gyrus, temporal pole, orbital sulcus, and inferior temporal sulcus.

Kjølhede T, Siemonsen S, Wenzel D, et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult Scler. 2017 Jul 1 [Epub ahead of print].

Noninvasive Device Measures Intracranial Pressure

A noninvasive device measures intracranial pressure (ICP) accurately, according to research published online ahead of print August 8 in the Journal of Neurosurgery. In patients with traumatic brain injury and subarachnoid hemorrhage who were undergoing treatment in a neurocritical intensive care unit, researchers recorded ICP using the gold-standard method of invasive external ventricular drainage or intraparenchymal monitoring. In addition, the authors simultaneously measured ICP noninvasively with a device that uses advanced signal-analysis algorithms for acoustic signals propagating through the cranium. Data were collected in 14 patients, yielding 2,543 data points of continuous parallel ICP values. For measurements at the ≥ 17-mm Hg cutoff, the sensitivity and specificity of the noninvasive device were 0.7541 and 0.8887, respectively. ICP values obtained using noninvasive and invasive monitoring methods correlated well.

Ganslandt O, Mourtzoukos S, Stadlbauer A, et al. Evaluation of a novel noninvasive ICP monitoring device in patients undergoing invasive ICP monitoring: preliminary results. J Neurosurg. 2017 Aug 8 [Epub ahead of print].

Strokes Decline Among Men, But Not Women

The rate of stroke in the US has declined among men, but not among women, according to a study published online ahead of print August 9 in Neurology. Researchers collected data on 1.3 million adults in Ohio and Kentucky between 1993 and 2010. They used medical records to identify first-ever strokes during four one-year periods. The researchers observed 7,710 incident strokes in the four periods, and 57% of them were among women. The incidence of all strokes decreased over time in men (263 to 192), but not in women (217 to 198). The researchers found a similar sex difference in the change in the rate of ischemic stroke (ie, a decline from 238 to 165 among men, and a change from 193 to 173 among women).

Madsen TE, Khoury J, Alwell K, et al. Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study. Neurology. 2017 Aug 9 [Epub ahead of print].

Link Between Alcohol Intake and Cognitively Healthy Longevity

Older adults who consume alcohol moderately on a regular basis are more likely to live to age 85 without dementia or other cognitive impairments than nondrinkers, according to a study published in the August issue of the Journal of Alzheimer’s Disease. Researchers examined 1,344 older community-dwelling adults and assessed alcohol intake by questionnaire in 1984–1987. They evaluated cognitive function in approximately four-year intervals between 1988 and 2009. About 49% of participants reported moderate alcohol intake, and 48% reported drinking almost daily. Relative to nondrinkers, moderate and heavy drinkers had significantly higher adjusted odds of survival to age 85 without cognitive impairment. Near-daily drinkers had two- to threefold higher adjusted odds of cognitively healthy longevity versus living to at least age 85 with cognitive impairment or death before age 85.

Richard EL, Kritz-Silverstein D, Laughlin GA, et al. Alcohol intake and cognitively healthy longevity in community-dwelling adults: The Rancho Bernardo Study. J Alzheimers Dis. 2017;59(3):803-814.

MRI Shows Brain Differences in Genetic Autism

In two genetically related cohorts at high risk for autism, reciprocal neuroanatomic abnormalities were associated with cognitive and behavioral impairments, according to a study published online ahead of print August 8 in Radiology. Researchers performed MRI on 79 carriers of a deletion at 16p11.2, 79 carriers of a duplication at 16p11.2, 64 unaffected family members, and 109 controls. The participants completed cognitive and behavioral tests, and neuroradiologists reviewed the images for development-related abnormalities. The researchers found differences in the brain structures of deletion and duplication carriers, compared with noncarriers. Deletion carriers had brain overgrowth, and duplication carriers had brain undergrowth. When investigators compared cognitive assessments to imaging findings, they found that any imaging feature associated with the deletion carriers indicated worse daily living, communication, and social skills.

Owen JP, Bukshpun P, Pojman N, et al. Brain MR imaging findings and associated outcomes in carriers of the reciprocal copy number variation at 16p11.2. Radiology. 2017 Aug 8 [Epub ahead of print].

FDA Clears Stimpod NMS460 for Relief of Chronic Pain

The FDA has cleared Stimpod NMS460, a noninvasive neuromodulation device, for the symptomatic relief and management of chronic intractable pain. The unit also can be used for the adjunctive treatment of postsurgical pain, posttraumatic acute pain, and pain control due to rehabilitation. The device has a pulsed radio frequency waveform that creates electromagnetic effects similar to those of invasive pulsed radio frequency treatments. Treatment is applied transcutaneously. Case studies have shown quick and notable relief of chronic intractable pain. The treatment has no known side effects. The Stimpod NMS460 also incorporates nerve-locating technology that includes a nerve-mapping probe that enables practitioners to evaluate the treatment progress of damaged nerves. Xavant Technology, which markets Stimpod NMS460, is headquartered in Pretoria, South Africa.

Longer Sleep Is Associated With Lower BMI

Adults who have poor sleep patterns are more likely to be overweight or obese and have poorer metabolic health, according to a study published July 27 in PLoS One. Researchers analyzed associations between sleep duration and adiposity, selected metabolic health markers, and diet using National Diet and Nutrition Survey data. In all, 1,615 adults (57.1% female) between ages 19 and 65 completed questions about sleep duration and three to four days of food diaries. Investigators recorded blood pressure and waist circumference. Fasting blood lipids, glucose, glycated hemoglobin, thyroid hormones, and high-sensitivity C-reactive protein were measured in a subset of participants. After adjusting for age, ethnicity, sex, smoking, and socioeconomic status, sleep duration was negatively associated with BMI and waist circumference. Sleep duration was positively associated with high-density lipoprotein cholesterol.

Potter GDM, Cade JE, Hardie LJ. Longer sleep is associated with lower BMI and favorable metabolic profiles in UK adults: findings from the National Diet and Nutrition Survey. PLoS One. 2017; 12(7):e0182195.

Can Bleeding Risk After Stroke Be Predicted?

The S2TOP-BLEED score can estimate three-year major bleeding risk in patients with transient ischemic attack (TIA) or ischemic stroke who use antiplatelet agents, according to a study published online ahead of print August 2 in Neurology. To develop this prediction model, researchers combined data from six trials investigating antiplatelet therapy after TIA or ischemic stroke. They performed Cox regression analyses stratified by trial to study the association between predictors and major bleeding. Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed three-year risk of major bleeding was 4.6%. The investigators identified male sex, smoking, type of antiplatelet agents, outcome on modified Rankin Scale ≥ 3, prior stroke, high blood pressure, lower BMI, elderly status, Asian ethnicity, and diabetes as predictors of major bleeding.

Hilkens NA, Algra A, Diener HC, et al. Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets: S2TOP-BLEED. Neurology. 2017 Aug 2 [Epub ahead of print].

Questionnaires Predict Survival in MS

The way patients with multiple sclerosis (MS) answer questionnaires could help to predict their survival rate from the disease, according to a study published July 10 in PLoS Medicine. From July 15, 2004, onward, 2,126 people with MS completed MS Impact Scale-29 (MSIS-29) questionnaires. By 2014, 264 participants had died. Higher baseline MSIS-29 physical score and higher baseline MSIS-29 psychologic score were associated with reduced survival time. In participants with high baseline MSIS-29 scores, mortality risk was greater if the MSIS-29 score worsened over one year. MSIS-29 physical scores were associated with survival time, independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis.

Raffel J, Wallace A, Gveric D, et al. Patient-reported outcomes and survival in multiple sclerosis: a 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29. PLoS Med. 2017;14(7):e1002346.

—Kimberly Williams

Statin Prescription Varies in Stroke Belt

Less than half of patients with stroke discharged from the hospital receive a prescription for statins, and the likelihood of a prescription varies by patients’ location, sex, age, and race, according to a study published August 2 in the Journal of the American Heart Association. Researchers analyzed discharge medications for 323 participants hospitalized for an ischemic stroke during follow-up of the Reasons for Geographic and Racial Differences in Stroke study. In the Stroke Belt, participants ages 65 and older were 47% less likely to be discharged on a statin, compared with people younger than 65. Compared with women, men in the Stroke Belt were 31% less likely to be discharged on a statin, while men outside the Stroke Belt were more likely to be discharged on a statin.

Albright KC, Howard VJ, Howard G, et al. Age and sex disparities in discharge statin prescribing in the stroke belt: evidence from the Reasons for Geographic and Racial Differences in Stroke Study. J Am Heart Assoc. 2017;6(8).

Midlife Vascular Risk Factors Increase Risk of Dementia

Midlife vascular risk factors are associated with increased risk of dementia in blacks and whites, according to a study published online ahead of print August 7 in JAMA Neurology. In the Atherosclerosis Risk in Communities study, investigators measured demographic and vascular risk factors at baseline (ie, obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia), along with the presence of the APOE ε4 genotype. After the baseline visit, participants had four additional in-person visits. In all, 1,516 cases of dementia (57.0% female and 34.9% black, with a mean age at visit 1 of 57.4) were identified among 15,744 participants. Black race, older age, lower educational attainment, and APOE ε4 genotype were associated with increased risk of dementia, as were midlife smoking, diabetes, prehypertension, and hypertension.

Gottesman RF, Albert MS, Alonso A, et al. Associations between midlife vascular risk factors and 25-year incident dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort. JAMA Neurol. 2017 August 7 [Epub ahead of print].

Resistance Training May Slow the Progression of MS

Progressive resistance training may have a neuroprotective or neuroregenerative effect in relapsing-remitting multiple sclerosis (MS), according to a study published online ahead of print July 1 in Multiple Sclerosis Journal. This study was a 24-week randomized controlled crossover trial. Participants were assigned to training or to a wait list. Assessments included disability measures and MRI. The MS Functional Composite score improved in the training group, but disability, lesion load, and global brain volumes did not differ between groups. The researchers noted higher absolute cortical thickness values in 19 of 74 investigated cortical regions after progressive resistance training. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups in the anterior cingulate gyrus, temporal pole, orbital sulcus, and inferior temporal sulcus.

Kjølhede T, Siemonsen S, Wenzel D, et al. Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis? Mult Scler. 2017 Jul 1 [Epub ahead of print].

Noninvasive Device Measures Intracranial Pressure

A noninvasive device measures intracranial pressure (ICP) accurately, according to research published online ahead of print August 8 in the Journal of Neurosurgery. In patients with traumatic brain injury and subarachnoid hemorrhage who were undergoing treatment in a neurocritical intensive care unit, researchers recorded ICP using the gold-standard method of invasive external ventricular drainage or intraparenchymal monitoring. In addition, the authors simultaneously measured ICP noninvasively with a device that uses advanced signal-analysis algorithms for acoustic signals propagating through the cranium. Data were collected in 14 patients, yielding 2,543 data points of continuous parallel ICP values. For measurements at the ≥ 17-mm Hg cutoff, the sensitivity and specificity of the noninvasive device were 0.7541 and 0.8887, respectively. ICP values obtained using noninvasive and invasive monitoring methods correlated well.

Ganslandt O, Mourtzoukos S, Stadlbauer A, et al. Evaluation of a novel noninvasive ICP monitoring device in patients undergoing invasive ICP monitoring: preliminary results. J Neurosurg. 2017 Aug 8 [Epub ahead of print].

Strokes Decline Among Men, But Not Women

The rate of stroke in the US has declined among men, but not among women, according to a study published online ahead of print August 9 in Neurology. Researchers collected data on 1.3 million adults in Ohio and Kentucky between 1993 and 2010. They used medical records to identify first-ever strokes during four one-year periods. The researchers observed 7,710 incident strokes in the four periods, and 57% of them were among women. The incidence of all strokes decreased over time in men (263 to 192), but not in women (217 to 198). The researchers found a similar sex difference in the change in the rate of ischemic stroke (ie, a decline from 238 to 165 among men, and a change from 193 to 173 among women).

Madsen TE, Khoury J, Alwell K, et al. Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study. Neurology. 2017 Aug 9 [Epub ahead of print].

Link Between Alcohol Intake and Cognitively Healthy Longevity

Older adults who consume alcohol moderately on a regular basis are more likely to live to age 85 without dementia or other cognitive impairments than nondrinkers, according to a study published in the August issue of the Journal of Alzheimer’s Disease. Researchers examined 1,344 older community-dwelling adults and assessed alcohol intake by questionnaire in 1984–1987. They evaluated cognitive function in approximately four-year intervals between 1988 and 2009. About 49% of participants reported moderate alcohol intake, and 48% reported drinking almost daily. Relative to nondrinkers, moderate and heavy drinkers had significantly higher adjusted odds of survival to age 85 without cognitive impairment. Near-daily drinkers had two- to threefold higher adjusted odds of cognitively healthy longevity versus living to at least age 85 with cognitive impairment or death before age 85.

Richard EL, Kritz-Silverstein D, Laughlin GA, et al. Alcohol intake and cognitively healthy longevity in community-dwelling adults: The Rancho Bernardo Study. J Alzheimers Dis. 2017;59(3):803-814.

MRI Shows Brain Differences in Genetic Autism

In two genetically related cohorts at high risk for autism, reciprocal neuroanatomic abnormalities were associated with cognitive and behavioral impairments, according to a study published online ahead of print August 8 in Radiology. Researchers performed MRI on 79 carriers of a deletion at 16p11.2, 79 carriers of a duplication at 16p11.2, 64 unaffected family members, and 109 controls. The participants completed cognitive and behavioral tests, and neuroradiologists reviewed the images for development-related abnormalities. The researchers found differences in the brain structures of deletion and duplication carriers, compared with noncarriers. Deletion carriers had brain overgrowth, and duplication carriers had brain undergrowth. When investigators compared cognitive assessments to imaging findings, they found that any imaging feature associated with the deletion carriers indicated worse daily living, communication, and social skills.

Owen JP, Bukshpun P, Pojman N, et al. Brain MR imaging findings and associated outcomes in carriers of the reciprocal copy number variation at 16p11.2. Radiology. 2017 Aug 8 [Epub ahead of print].

FDA Clears Stimpod NMS460 for Relief of Chronic Pain

The FDA has cleared Stimpod NMS460, a noninvasive neuromodulation device, for the symptomatic relief and management of chronic intractable pain. The unit also can be used for the adjunctive treatment of postsurgical pain, posttraumatic acute pain, and pain control due to rehabilitation. The device has a pulsed radio frequency waveform that creates electromagnetic effects similar to those of invasive pulsed radio frequency treatments. Treatment is applied transcutaneously. Case studies have shown quick and notable relief of chronic intractable pain. The treatment has no known side effects. The Stimpod NMS460 also incorporates nerve-locating technology that includes a nerve-mapping probe that enables practitioners to evaluate the treatment progress of damaged nerves. Xavant Technology, which markets Stimpod NMS460, is headquartered in Pretoria, South Africa.

Longer Sleep Is Associated With Lower BMI

Adults who have poor sleep patterns are more likely to be overweight or obese and have poorer metabolic health, according to a study published July 27 in PLoS One. Researchers analyzed associations between sleep duration and adiposity, selected metabolic health markers, and diet using National Diet and Nutrition Survey data. In all, 1,615 adults (57.1% female) between ages 19 and 65 completed questions about sleep duration and three to four days of food diaries. Investigators recorded blood pressure and waist circumference. Fasting blood lipids, glucose, glycated hemoglobin, thyroid hormones, and high-sensitivity C-reactive protein were measured in a subset of participants. After adjusting for age, ethnicity, sex, smoking, and socioeconomic status, sleep duration was negatively associated with BMI and waist circumference. Sleep duration was positively associated with high-density lipoprotein cholesterol.

Potter GDM, Cade JE, Hardie LJ. Longer sleep is associated with lower BMI and favorable metabolic profiles in UK adults: findings from the National Diet and Nutrition Survey. PLoS One. 2017; 12(7):e0182195.

Can Bleeding Risk After Stroke Be Predicted?

The S2TOP-BLEED score can estimate three-year major bleeding risk in patients with transient ischemic attack (TIA) or ischemic stroke who use antiplatelet agents, according to a study published online ahead of print August 2 in Neurology. To develop this prediction model, researchers combined data from six trials investigating antiplatelet therapy after TIA or ischemic stroke. They performed Cox regression analyses stratified by trial to study the association between predictors and major bleeding. Major bleeding occurred in 1,530 of the 43,112 patients during 94,833 person-years of follow-up. The observed three-year risk of major bleeding was 4.6%. The investigators identified male sex, smoking, type of antiplatelet agents, outcome on modified Rankin Scale ≥ 3, prior stroke, high blood pressure, lower BMI, elderly status, Asian ethnicity, and diabetes as predictors of major bleeding.

Hilkens NA, Algra A, Diener HC, et al. Predicting major bleeding in patients with noncardioembolic stroke on antiplatelets: S2TOP-BLEED. Neurology. 2017 Aug 2 [Epub ahead of print].

Questionnaires Predict Survival in MS

The way patients with multiple sclerosis (MS) answer questionnaires could help to predict their survival rate from the disease, according to a study published July 10 in PLoS Medicine. From July 15, 2004, onward, 2,126 people with MS completed MS Impact Scale-29 (MSIS-29) questionnaires. By 2014, 264 participants had died. Higher baseline MSIS-29 physical score and higher baseline MSIS-29 psychologic score were associated with reduced survival time. In participants with high baseline MSIS-29 scores, mortality risk was greater if the MSIS-29 score worsened over one year. MSIS-29 physical scores were associated with survival time, independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis.

Raffel J, Wallace A, Gveric D, et al. Patient-reported outcomes and survival in multiple sclerosis: a 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29. PLoS Med. 2017;14(7):e1002346.

—Kimberly Williams