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Abstract Objective To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication‐overuse headache (MOH). Background Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene‐related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH. Methods PROMISE‐2 (NCT02974153) was a double‐blind, randomized, placebo‐controlled, phase 3 study that comprised a screening visit, a 28‐day pretreatment period, and a 32‐week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1–12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1–24. Results There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg ( n = 139), 300 mg ( n = 147), or placebo ( n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1–12, eptinezumab‐treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = −8.4, difference from placebo [95% confidence interval (CI)] = −3.0 [−4.56, −1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = −8.6, difference from placebo [95% CI] = −3.2 [−4.66, −1.78], p < 0.0001 vs. placebo; placebo, −5.4). Compared with placebo, more eptinezumab‐treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1–12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24‐week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo‐treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication‐overuse thresholds. Conclusions In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.

Objective To determine the onset of preventive efficacy with eptinezumab in patients with migraine. Background Eptinezumab is a monoclonal antibody inhibiting calcitonin gene‐related peptide approved as an intravenously administered treatment for the prevention of migraine. Methods Patients who received eptinezumab 100 mg, eptinezumab 300 mg, or placebo in PROMISE7‐1 (episodic migraine; 100 mg, n = 221; 300 mg, n = 222; placebo, n = 222) or PROMISE7‐2 (chronic migraine; 100 mg, n = 356; 300 mg, n = 350; placebo, n = 366) were included. Testing of the percentage of patients with a migraine on day 1 after dosing was prespecified and alpha‐controlled. In further exploration of this prespecified endpoint, a post hoc closed testing procedure, which controlled the false‐positive (type 1) error rate, provided a statistically rigorous evaluation of migraine prevention onset. The procedure involved up to 84 tests of significance, all of which were performed in sequence until the first nonsignificant result. Results For both studies, all tests for significance for eptinezumab 100 and 300 mg, from days 1‐84 through day 1 alone, achieved nominal significance ( P < .05), indicating that eptinezumab was fully effective beginning on day 1. Over each interval, the treatment effect was comparable to the effect over weeks 1‐12. Mean changes from baseline in monthly migraine days for the primary endpoint period ranged from −3.9 to −4.9, −4.1 to −4.9, and −2.2 to −3.2 for eptinezumab 100, 300 mg, and placebo, respectively, in PROMISE7‐1 and from −7.2 to −8.0, −7.9 to −8.2, and −4.3 to −5.6, respectively, in PROMISE7‐2. The difference from placebo (95% confidence interval) in day 1 treatment effect was −2.2 (−4.1, −0.3) and −2.5 (−4.4, −0.6) days/month for eptinezumab 100 and 300 mg, respectively, in PROMISE7‐1, and was −3.8 (−5.6, −2.0) and −4.0 (−5.8, −2.1) days/month for 100 and 300 mg, respectively, in PROMISE7‐2. Conclusions The migraine preventive effect of eptinezumab is rapid and sustained in patients with episodic or chronic migraine, with onset of optimal preventive efficacy observed on the day following the initial dose.

Bioactive surfaces and materials have displayed great potential in a variety of tissue engineering applications but often struggle to completely emulate complex bodily systems. The extracellular matrix (ECM) is a crucial, bioactive component in all tissues and has recently been identified as a potential solution to be utilized in combination with biomaterials. In tissue engineering, the ECM can be utilized in a variety of applications by employing the biochemical and biomechanical cues that are crucial to regenerative processes. However, viable solutions for maintaining the dimensionality, spatial orientation, and protein composition of a naturally cell-secreted ECM remain challenging in tissue engineering. Therefore, this work used soft lithography to create micropatterned polydimethylsiloxane (PDMS) substrates of a three-dimensional nature to control cell adhesion and alignment. Cells aligned on the micropatterned PDMS, secreted and assembled an ECM, and were decellularized to produce an aligned matrix biomaterial. The cells seeded onto the decellularized, patterned ECM showed a high degree of alignment and migration along the patterns compared to controls. This work begins to lay the groundwork for elucidating the immense potential of a natural, cell-secreted ECM for directing cell function and offers further guidance for the incorporation of natural, bioactive components for emerging tissue engineering technologies.

Abstract Purpose: Despite therapeutic advancements, biological markers that predict the natural history of primary central nervous system lymphoma (PCNSL) are lacking and age and performance status are the only consistently identified independent prognostic variables. BCL6 rearrangements and deletion of the tumor suppressor gene R-PTP-κ (PTPRK) at 6q22 are thought to be common genetic abnormalities in PCNSL but their prognostic significance is unknown. The aim of this study is to determine the prevalence and survival impact of del(6)(q22), BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements and prevalence of Epstein-Barr virus (EBV) infection in PCNSL affecting immunocompetent patients. Patients and methods: Seventy-six specimens from 76 HIV-negative, immunocompetent patients with PCNSL newly diagnosed and treated at Mayo Clinic between 1985 and 2006 were studied. Interphase fluorescence in-situ hybridization (FISH) was performed using two-color break apart probes (BAP) for BCL6 and MYC, a two-color dual-fusion probe for IGH-BCL6, and a two-color probe for del(6)(q22) on thin sections of paraffin-embedded tumor samples. Two-color IGH BAP FISH probes were also used to confirm IGH rearrangements in cases showing extra IGH signals without fusion using the IGH-BCL6 probe. In situ hybridization was performed using probes that recognize EBV-encoded RNA (EBER) on paraffin-embedded tumor samples. Survival data were analyzed for patients diagnosed after 1997 (n=53), corresponding to the change to high dose methotrexate as the standard of care. Survival was calculated from the date of tissue diagnosis to date of death or last contact. Survival curves were estimated using the Kaplan-Meier method. The log-rank test was used to compare survival across groups. Two-tailed p-values &lt;0.05 were considered statistically significant. Clinical information for the 1985–2006 and 1997–2006 groups was comparable, including median age (67 years (y) vs 68 y), age range (26–87 y for both groups), percentage of deaths (67 vs 64) and median follow up for survivors (588 d vs 395 d). Results: Thirty-four (45%) cases showed del(6)(q22), 6 of which alsocontained a BCL6 rearrangement. Seventeen (22%) cases had a BCL6 rearrangement. Translocations involving IGH and an unknown partner gene (n=2) and MYC and an unknown partner gene (n=2) were also identified. All cases were EBER negative. Of the 53 patients diagnosed after 1997, 23 lacked del(6)(q22) or BCL6 rearrangement and had a median overall survival (MS) of 731 days (d). The 17 patients with an isolated del(6)(q22) had a MS of 90 d and the 13 patients with a BCL6 rearrangement had a MS of 442 d (p=0.0016). Conclusions: Del(6)(q22) and BCL6 rearrangements are common in PCNSL (45% and 22% of cases, respectively) and are associated with decreased survival, particularly del(6)(q22) seemingly independent of patient age and treatment time trends. IGH translocations were less frequent than in systemic diffuse large B-cell lymphoma (13% vs 51%), suggesting a distinct pathogenesis. MYC translocations and EBV infection are rare in PCNSL affecting immunocompetent patients.

PCNSL molecular pathogenesis in immunocompetent patients is largely unknown. Small studies suggest a role for immunoglobulin heavy chain (IGH) gene translocations. We studied the incidence of IGH, BCL6, and MYC gene rearrangements in 44 PCNSL affecting immunocompetent patients, diagnosed and treated at Mayo Clinic (1992–2006). All cases were DLBL according to the WHO classification, confined to the CNS. Interphase fluorescence in‐situ hybridization (FISH) was performed using a two‐color IGH‐BCL6 dual‐fusion probe and a two‐color MYC breakapart (BAP) probe on paraffin‐embedded tumor samples. Two‐color BCL6 or IGH BAP FISH probes were also used in cases showing extra FISH signals other than IGH‐BCL6 fusion. Sufficient tumor cells for FISH analysis using the IGH‐BCL6 and MYC probes were available in 43 and 39 cases, respectively. IGH‐BCL6 fusion was present in 6 (14%) cases, one also with a separated MYC signal. Three (7%) cases showed 3 intact BCL6 signals using both the IGH‐BCL6 and BCL6 BAP probes, indicating trisomy 3. One (2%) showed 3 intact IGH signals using both the IGH‐BCL6 and IGH BAP probes, indicating trisomy 14. Remaining 33 (77%) cases lacked abnormalities involving IGH, BCL6 or MYC. IGH‐BCL6 fusion was present in 14% of cases, 1 of which also had a translocation involving MYC and an unknown partner gene. All other cases lacked translocations involving IGH, BCL6, and MYC. The frequency of IGH‐BCL6 translocations in PCNSL is less than that seen in systemic DLBCL. Other translocations involving IGH that are not uncommon in systemic DLBCL, such as IGH‐BCL2 and IGH‐MYC, are rare to absent in PCNSL, suggesting a distinct pathogenesis for PCNSL compared to systemic DLBCL.

Background Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, for the prevention of chronic migraine. Objective To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program. Methods This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Results The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo ( p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo. Conclusions The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention. Trial Registration ClinicalTrials.gov identifier: NCT02275117.

BACKGROUND: An increasing proportion of pediatric hospital days are attributed to technology-dependent children. The impact that a pediatric home care nursing (HCN) shortage has on increasing length of hospital stay and readmissions in this population is not well documented. METHODS: We conducted a 12-month multisite prospective study of children with medical complexity discharging with home health. We studied the following 2 cohorts: new patients discharging for the first time to home nursing and existing patients discharging from the hospital to previously established home nursing. A modified delay tool was used to categorize causes, delayed discharge (DD) days, and unplanned 90-day readmissions. RESULTS: DD occurred in 68.5% of 54 new patients and 9.2% of 131 existing patients. Lack of HCN was the most frequent cause of DD, increasing costs and directly accounting for an average length of stay increase of 53.9 days (range: 4–204) and 35.7 days (3–63) for new and existing patients, respectively. Of 1582 DDs, 1454 (91.9%) were directly attributed to lack of HCN availability. DD was associated with younger age and tracheostomy. Unplanned 90-day readmissions were due to medical setbacks (96.7% of cases) and occurred in 53.7% and 45.0% of new and existing patients, respectively. CONCLUSIONS: DD and related costs are primarily associated with shortage of HCN and predominantly affect patients new to HCN. Medical setbacks are the most common causes of unplanned 90-day readmissions. Increasing the availability of home care nurses or postacute care facilities could reduce costly hospital length of stay.

Objective: The study sought to evaluate whether topiramate prevents development of chronic daily headache (CDH, ≥15 headache days per month) in adult subjects with high-frequency episodic migraine (HFEM, 9–14 migraine headache days/month). A secondary objective was to assess the efficacy of topiramate as preventive migraine treatment in this population. Methods: This was a multicenter, randomized, double-blind, placebo-controlled study comparing topiramate 100 mg/day and placebo for 26 weeks. The primary efficacy variable was new-onset CDH at month 6. Secondary efficacy measures included migraine and headache days. Adverse events (AEs) were evaluated. Results: A total of 159 topiramate subjects and 171 placebo subjects were efficacy-evaluable. At month 6, 1.4% of topiramate subjects versus 2.3% of placebo subjects had CDH ( p = .589). Compared with placebo, topiramate treatment was associated with statistically significant reductions in mean number of migraine days (6.6 vs. 5.3/28 days; p = .001) and headache days (6.6 vs 5.3/28 days; p = .001). Most commonly reported AEs in the topiramate versus placebo group included paresthesia (32.4% vs. 7.0%), fatigue (14.8% vs. 8.6%), dizziness (11.4% vs. 7.6%) and nausea (10.8% vs. 9.2%). Conclusion: Topiramate 100 mg/day did not prevent the development of CDH at six months in subjects with HFEM. Topiramate was effective in reducing headache days and migraine headache days and generally well tolerated.

Purpose Primary CNS lymphoma (PCNSL) is an aggressive lymphoma but clinically validated biologic markers that can predict natural history to tailor treatment according to risk are lacking. Several genetic changes including BCL6 rearrangements and deletion of 6q22, containing the putative tumor suppressor gene PTPRK, are potential risk predictors. Herein we determined the prevalence and survival impact of del(6)(q22) and BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements in a large PCNSL cohort treated in a single center. Patients and Methods Interphase fluorescence in situ hybridization was performed using two-color probes for BCL6, MYC, IGH-BCL6, and del(6)(q22) on thin sections of 75 paraffin-embedded samples from 75 HIV-negative, immunocompetent patients newly diagnosed with PCNSL. Survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and proportional hazards regression adjusting for age, deep structure involvement, and high-dose methotrexate (HDMTX) treatment. Results The prevalence of del(6)(q22) and BCL6, IGH, and MYC translocations was 45%,17%, 13%, and 3%, respectively. The presence of del(6)(q22) and/or a BCL6 translocation was associated with inferior overall survival (OS; P = .0097). The presence of either del(6)(q22) alone or a BCL6 translocation alone was also associated with inferior OS (P = .0087). Univariable results held after adjusting for age, deep structure involvement, and HDMTX. Conclusion Del (6)(q22) and BCL6 rearrangements are common in PCNSL and predict for decreased OS independent of deep structure involvement and HDMTX. Unlike systemic diffuse large B-cell lymphoma, del(6)(q22) is common and IGH translocations are infrequent and usually involve BCL6 rather than BCL2, suggesting a distinct pathogenesis.

While “sinus” headache is a widely accepted clinical diagnosis, many medical specialists consider it to be an uncommon cause of recurrent headaches. Unnecessary diagnostic studies, surgical interventions, and medical treatments are often the result of the inappropriate diagnosis of sinus headache. Both the International Headache Society and the American Academy of Otolaryngology–Head and Neck Surgery have attempted to characterize conditions leading to headaches of rhinogenic origin. However, they have done so from different perspectives and in isolation from the other specialty groups. An interdisciplinary ad hoc committee recently convened to discuss the role of sinus disease and the nose in the etiology of headache and to review recent epidemiologic studies suggesting that sinus headache (headache of rhinogenic origin) and migraine are frequently confused with one another. Clinical trial data are presented which clearly indicate that the majority of sinus headaches can actually be classified as migraines. This committee reviewed scientific evidence available from multiple disciplines and concludes that considerable research and clinical study are needed to further understand and explain the role of nasal pathology and autonomic activation in migraine and headaches of rhinogenic origin. However, there was a consensus from this group that greater diagnostic and therapeutic attention needs to be given to patients complaining of sinus headache that may indeed be due to the nose.