Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

Real-world treatments and thrombotic events in polycythemia vera patients in the USA.

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with increased risk of thrombotic events (TE) and death. Therapeutic interventions, phlebotomy and cytoreductive medications, are targeted to maintain hematocrit levels < 45% to prevent adverse outcomes. This retrospective observational study examined medical and pharmacy claims of 28,306 PV patients initiating treatment for PV in a data period inclusive of 2011 to 2019. Study inclusion required ≥ 2 PV diagnosis codes in the full data period, at least 1 year of PV treatment history, and ≥ 1 prescription claim and medical claim in both 2018 and 2019. Patients having ≥ 2 hematocrit (HCT) test results in linked outpatient laboratory data (2018-2019) were designated as the HCT subgroup (N = 4246). Patients were characterized as high- or low-risk at treatment initiation based on age and prior thrombotic history. The majority of patients in both risk groups (60% of high-risk and 83% of low-risk) initiated treatment with phlebotomy monotherapy, and during a median follow-up period of 808 days, the vast majority (81% low-risk, 74% high-risk) maintained their original therapy during the follow-up period. Hematocrit control was suboptimal in both risk groups; 54% of high-risk patients initiating with phlebotomy monotherapy sometimes/always had HCT levels > 50%; among low-risk patients, 64% sometimes/always had HCT levels above 50%. Overall, 16% of individuals experienced at least 1 TE subsequent to treatment initiation, 20% (n = 3920) among high-risk and 8% (n = 629) among low-risk patients. This real-world study suggests that currently available PV treatments may not be used to full advantage.

CAPER: patient preferences to inform nonsurgical treatment of chronic low back pain: a discrete-choice experiment.

OBJECTIVE: We developed and used a discrete-choice measure to study patient preferences with regard to the risks and benefits of nonsurgical treatments when they are making treatment selections for chronic low back pain. METHODS: "CAPER TREATMENT" (Leslie Wilson) was developed with standard choice-based conjoint procedures (discrete-choice methodology that mimics an individual's decision-making process). After expert input and pilot testing, our final measure had 7 attributes (chance of pain relief, duration of relief, physical activity changes, treatment method, treatment type, treatment time burden, and risks of treatment) with 3-4 levels each. Using Sawtooth software (Sawtooth Software, Inc., Provo, UT, USA), we created a random, full-profile, balanced-overlap experimental design. Respondents (n = 211) were recruited via an emailed online link and completed 14 choice-based conjoint choice pairs; 2 fixed questions; and demographic, clinical, and quality-of-life questions. Analysis was performed with random-parameters multinomial logit with 1000 Halton draws. RESULTS: Patients cared most about the chance of pain relief, followed closely by improving physical activity, even more than duration of pain relief. There was comparatively less concern about time commitment and risks. Gender and socioeconomic status influenced preferences, especially with relation to strength of expectations for outcomes. Patients experiencing a low level of pain (Pain, Enjoyment, and General Activity Scale [PEG], question 1, numeric rating scale score<4) had a stronger desire for maximally improved physical activity, whereas those in a high level of pain (PEG, question 1, numeric rating scale score>6) preferred both maximum and more limited activity. Highly disabled patients (Oswestry Disability Index score>40) demonstrated distinctly different preferences, placing more weight on achieving pain control and less on improving physical activity. CONCLUSIONS: Individuals with chronic low back pain were willing to trade risks and inconveniences for better pain control and physical activity. Additionally, different preference phenotypes exist, which suggests a need for clinicians to target treatments to particular patients.

Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.

BACKGROUND: FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD). METHODS: In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed. RESULTS: In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects. CONCLUSIONS: FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.

FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis.

FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway.

Current trends in rotator cuff repair: surgical technique, setting, and cost.

PURPOSE: The purpose of this study was to evaluate national trends in the surgical setting and hospital costs of shoulder arthroscopy and rotator cuff repair (RCR) using the Florida State surgical database and national inpatient database. METHODS: In part I we analyzed population-adjusted shifts in RCR technique (arthroscopic v open) in the Florida surgical database from 2000-2007 and quantified the procedural codes associated with arthroscopic and open RCR. In part II we analyzed the Nationwide Inpatient Sample database from 2001-2009 for the total number of inpatient RCRs, the inpatient hospital type (rural, urban non-teaching, or urban teaching), and the cost. RESULTS: Part I showed a 163% increase in outpatient procedures in Florida, with a 353% increase in arthroscopic RCRs. There was a concurrent decrease in open RCRs; however, the overall trend was a 2-fold increase in total RCRs. Associated procedures such as subacromial decompression, distal clavicle resection, and extensive glenohumeral debridement increased by 440%, 589%, and 1,253%, respectively. Part II showed an overall 58.8% decrease in inpatient RCRs that was similar across all hospital settings, with an increase in RCR-associated hospital charges by 144.9%, whereas hospital costs only increased by 85.2%. CONCLUSIONS: The study confirms a shift toward arthroscopic RCR and associated procedures in the outpatient setting. The increased financial cost partly explains the shift; nevertheless, future studies are needed to further examine national trends. CLINICAL RELEVANCE: This study examining RCR trends by hospital type, cost, and setting further elucidates how orthopaedic surgery practice is evolving with the implementation of arthroscopic RCR in the past decade.

Hip arthroscopy: from the beginning to the future--an innovator's perspective.

Hip arthroscopy is one of the fastest-growing areas of orthopaedic surgery. There are many reasons for this, including a better understanding of the pathophysiology of damage to the hip joint, improvements in imaging and technology advancements in arthroscopic instrumentation. This manuscript documents the historical development of hip arthroscopy, in general, as well as advances and ideas that have led to common techniques with regard to portal placement, traction and instrumentation. These advances have led to expanding indications for hip arthroscopy. This manuscript ends with some thoughts about the future of hip arthroscopy from the perspective of one of the leaders who helped shape hip arthroscopy, as it is performed today.

Trends in hip arthroscopy utilization in the United States.

INTRODUCTION: The purpose of this study was to evaluate the changing incidence of hip arthroscopy procedures among newly trained surgeons in the United States, the indications for hip arthroscopy, and the reported rate of post-operative complications. METHODS: The ABOS database was used to evaluate the annual incidence of hip arthroscopy procedures between 2006-2010. Procedures were categorized by indication and type of procedure. The rate of surgical complications was calculated and compared between the published literature and hip arthroscopy procedures performed for femoroacetabular impingement (FAI)/osteoarthritis (OA) and for labral tears among the newly trained surgeon cohort taking the ABOS Part II Board exam. RESULTS: The overall incidence of hip arthroscopy procedures performed by ABOS Part II examinees increased by over 600% during the 5-year period under study from approximately 83 in 2006 to 636 in 2010. The incidence of hip arthroscopy for FAI/OA increased steadily over the time period under study, while the incidence of hip arthroscopy for labral tears was variable over time. The rate of surgical complications was 5.9% for hip arthroscopy procedures for a diagnosis of FAI/OA vs. 4.4% for a diagnosis of labral tear (P=0.36). CONCLUSIONS: The incidence of hip arthroscopy has increased dramatically over the past 5 years, particularly for the indication of FAI/OA. Reported surgical complication rates are relatively low, but appear higher than those rates reported in previously published series. Appropriate indications for hip arthroscopy remain unclear.

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial.

BACKGROUND: Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis. METHODS: This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965. FINDINGS: Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 µmol/L (95% CI 18·6 to 30·6), 20·1 µmol/L (14·8 to 25·3), 11·9 µmol/L (9·2 to 14·7), 22·5 µmol/L (15·9 to 29·1), and 19·0 µmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 µg/L (52·2 to 114.4), 65·5 µg/L (32·1 to 98·9), 62·8 µg/L (33·8 to 91·9), 150·0 µg/L (86·6 to 213.3), and 94·3 µg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment. INTERPRETATION: Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis. FUNDING: Protagonist Therapeutics.

Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of BHT-3009 in relapsing-remitting multiple sclerosis (MS) and to confirm that BHT-3009 causes immune tolerance. METHODS: BHT-3009 is a tolerizing DNA vaccine for MS, encoding full-length human myelin basic protein. Relapsing-remitting MS patients were randomized 1:1:1 into three groups: placebo, 0.5 mg BHT-3009, or 1.5 mg BHT-3009, given intramuscularly at weeks 0, 2, 4, and every 4 weeks thereafter until week 44. The primary end point was the 4-week rate of occurrence of new gadolinium-enhancing lesions on brain magnetic resonance images from weeks 28 to 48. Protein microarrays were used to measure levels of anti-myelin autoantibodies. RESULTS: Compared with placebo, in the 267 patient analysis population the median 4-week rate of new enhancing lesions during weeks 28 to 48 was 50% lower with 0.5 mg BHT-3009 (p = 0.07) and during weeks 8 to 48 was 61% lower with 0.5 mg BHT-3009 (p = 0.05). The mean volume of enhancing lesions at week 48 was 51% lower on 0.5 mg BHT-3009 compared with placebo (p = 0.02). No significant improvement in magnetic resonance imaging lesion parameters was observed with 1.5 mg BHT-3009. Dramatic reductions in 23 myelin-specific autoantibodies in the 0.5 mg BHT-3009 arm were observed, but not with placebo or 1.5 mg BHT-3009. CONCLUSIONS: In relapsing-remitting MS patients, treatment with the lower dose (0.5 mg) of BHT-3009 for 44 weeks nearly attained the primary end point for reduction of the rate of new enhancing magnetic resonance imaging lesions (p = 0.07) and achieved several secondary end points including a reduction of the rate of enhancing magnetic resonance imaging lesions from weeks 8 to 48 (p = 0.05). Immunological data in a preselected subgroup of patients also indicated that treatment with 0.5 mg induced antigen-specific immune tolerance. The greater dose was ineffective.

Local Application of Vancomycin in Spine Surgery Does Not Result in Increased Vancomycin-Resistant Bacteria-10-Year Data.

STUDY DESIGN: Case-control study. OBJECTIVES: To analyze the microbial flora in surgical spine infections and their antibiotic resistance patterns across time and determine the correlation between vancomycin application in the wound and vancomycin-resistant microbes. SUMMARY OF BACKGROUND DATA: Prior studies show a reduction in surgical site infections with intrawound vancomycin placement. No data are available on the potential negative effects of this intervention, in particular, whether there would be a resultant increase in vancomycin-resistant organisms or bacterial resistance profiles. METHODS: All culture-positive surgical site infections at a single institution were analyzed from 2007 to 2017. Each bacterium was assessed independently for resistance patterns. The two-tailed Fisher exact test was used to determine the correlation between vancomycin application and the presence of vancomycin-resistant bacteria, polymicrobial infections, or gram-negative bacterial infections. RESULTS: One hundred and eight bacteria were isolated from 113 surgical site infections from 2007 to 2017. The most common organisms were staphylococcus with varying resistance patterns and Escherichia coli. Vancomycin-resistant Enterococcus faecium was isolated in three infections. Out of the 4,878 surgical cases from 2011 to 2017, vancomycin was placed in 48.3%, and no vancomycin in 51.7%. There were 33 infections (1.4%) in the vancomycin group and 20 infections (0.8%) in the no-vancomycin group (χ2 = 0.0521). There was no correlation between vancomycin application in the wound and vancomycin-resistant microbes (χ2 = 0.2334) and polymicrobial infections (χ2 = 0.1328). There was an increased rate of gram-negative organisms in infections after vancomycin application in the wound versus no vancomycin (χ2 = 0.0254). CONCLUSIONS: Topical vancomycin within the surgical site is not correlated with vancomycin-resistant bacteria. However, there was an increased incidence of gram-negative organisms in infections after vancomycin application in the wound versus no vancomycin. Continued surveillance with prospectively collected randomized data is necessary to better understand bacterial evolution against current antimicrobial techniques. LEVEL OF EVIDENCE: Level III.

Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial.

OBJECTIVE: To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS). DESIGN: The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding. SETTING: The trial was conducted at 4 academic institutions within North America. Patients Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years. INTERVENTIONS: BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg). MAIN OUTCOME MEASURES: The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses. RESULTS: BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. CONCLUSION: In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.

Outcomes and effectiveness of posterior occipitocervical fusion for suboccipital spinal metastases.

OBJECTIVE The incidence of suboccipital spinal metastases is rare but has increased given cancer patients' longer life expectancies. Operative treatment in this region is often challenging because of limited fixation points due to tumor lysis, as well as adjacent neural and vascular anatomy. Few studies have reported on this population of cancer patients. The purpose of this study was to evaluate clinical outcomes and complications of patients with suboccipital spinal metastases who had undergone posterior occipitocervical fixation. METHODS A single-institution database was reviewed to identify patients with suboccipital metastases who had undergone posterior-only instrumented fusion between 1999 and 2014. Clinical presentation, perioperative complications, and postoperative results were analyzed. Pain was assessed using the visual analog scale. Survival analysis was performed using a Kaplan-Meier curve. The revised Tokuhashi and the Tomita scoring systems were used for prognosis prediction. RESULTS Fifteen patients were identified, 10 men and 5 women with mean age of 64.8 ± 11.8 years (range 48-80 years). Severe neck pain without neurological deficit was the most common presentation. Primary tumors included lung, breast, bladder, myeloma, melanoma, and renal cell cancers. All tumors occurred in the axis vertebra. Preoperative Tokuhashi and Tomita scores ranged from 5 to 13 and 3 to 7, respectively. All patients had undergone occipitocervical fusion of a mean of 4.6 levels (range 2-7 levels). Median survival was 10.3 months. In all cases, neck pain markedly improved and patients were able to resume activities of daily living. The average postoperative pain score was significantly improved as compared with the average preoperative score (1.90 ± 2.56 and 5.50 ± 2.99, respectively, p = 0.01). Three patients experienced postoperative medical complications including urinary tract infection, deep vein thrombosis, myocardial infarction, and cardiac arrhythmia. In the follow-up period, no wound infections or reoperations occurred and no patients experienced spinal cord deficits from tumor recurrence. CONCLUSIONS Posterior-only occipitocervical stabilization was highly effective at relieving patients' neck pain. No instrumentation failures were noted, and no neurological complications or tumor progression causing spinal cord deficits was noted in the follow-up period.

Outcomes following Laminoplasty or Laminectomy and Fusion in Patients with Myelopathy Caused by Ossification of the Posterior Longitudinal Ligament: A Systematic Review.

Study Design Systematic review. Objective To compare laminoplasty versus laminectomy and fusion in patients with cervical myelopathy caused by OPLL. Methods A systematic review was conducted using PubMed/Medline, Cochrane database, and Google scholar of articles. Only comparative studies in humans were included. Studies involving cervical trauma/fracture, infection, and tumor were excluded. Results Of 157 citations initially analyzed, 4 studies ultimately met our inclusion criteria: one class of evidence (CoE) II prospective cohort study and three CoE III retrospective cohort studies. The prospective cohort study found no significant difference between laminoplasty and laminectomy and fusion in the recovery rate from myelopathy. One CoE III retrospective cohort study reported a significantly higher recovery rate following laminoplasty. Another CoE III retrospective cohort study reported a significantly higher recovery rate in the laminectomy and fusion group. One CoE II prospective cohort study and one CoE III retrospective cohort study found no significant difference in pain improvement between patients treated with laminoplasty versus patients treated with laminectomy and fusion. All four studies reported a higher incidence of C5 palsy following laminectomy and fusion than laminoplasty. One CoE II prospective cohort and one CoE III retrospective cohort reported that there was no significant difference in axial neck pain between the two procedures. One CoE III retrospective cohort study suggested that there was no significant difference between groups in OPLL progression. Conclusion Data from four comparative studies was not sufficient to support the superiority of laminoplasty or laminectomy and fusion in treating cervical myelopathy caused by OPLL.

Lateral interbody fusion combined with open posterior surgery for adult spinal deformity.

OBJECTIVE Lateral interbody fusion (LIF) with percutaneous screw fixation can treat adult spinal deformity (ASD) in the coronal plane, but sagittal correction is limited. The authors combined LIF with open posterior (OP) surgery using facet osteotomies and a rod-cantilever technique to enhance lumbar lordosis (LL). It is unclear how this hybrid strategy compares to OP surgery alone. The goal of this study was to evaluate the combination of LIF and OP surgery (LIF+OP) for ASD. METHODS All thoracolumbar ASD cases from 2009 to 2014 were reviewed. Patients with < 6 months follow-up, prior fusion, severe sagittal imbalance (sagittal vertical axis > 200 mm or pelvic incidence-LL > 40°), and those undergoing anterior lumbar interbody fusion were excluded. Deformity correction, complications, and outcomes were compared between LIF+OP and OP-only surgery patients. RESULTS LIF+OP (n = 32) and OP-only patients (n = 60) had similar baseline features and posterior fusion levels. On average, 3.8 LIFs were performed. Patients who underwent LIF+OP had less blood loss (1129 vs 1833 ml, p = 0.016) and lower durotomy rates (0% vs 23%, p = 0.002). Patients in the LIF+OP group required less ICU care (0.7 vs 2.8 days, p < 0.001) and inpatient rehabilitation (63% vs 87%, p = 0.015). The incidence of new leg pain, numbness, or weakness was similar between groups (28% vs 22%, p = 0.609). All leg symptoms resolved within 6 months, except in 1 OP-only patient. Follow-up duration was similar (28 vs 25 months, p = 0.462). LIF+OP patients had significantly less pseudarthrosis (6% vs 27%, p = 0.026) and greater improvement in visual analog scale back pain (mean decrease 4.0 vs 1.9, p = 0.046) and Oswestry Disability Index (mean decrease 21 vs 12, p = 0.035) scores. Lumbar coronal correction was greater with LIF+OP surgery (mean [± SD] 22° ± 13° vs 14° ± 13°, p = 0.010). LL restoration was 22° ± 13°, intermediately between OP-only with facet osteotomies (11° ± 7°, p < 0.001) and pedicle subtraction osteotomy (29° ± 10°, p = 0.045). CONCLUSIONS LIF+OP is an effective strategy for ASD of moderate severity. Compared with the authors' OP-only operations, LIF+OP was associated with faster recovery, fewer complications, and greater relief of pain and disability.

A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies.

Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological, pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation. None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m(2)/day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation, hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely on this schedule, resulting in a maximum deliverable dose of 3.3 g/m(2)/day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.

Phase II trial of the histone deacetylase inhibitor pivaloyloxymethyl butyrate (Pivanex, AN-9) in advanced non-small cell lung cancer.

This multicenter phase II trial evaluated the therapeutic activity and safety profile of pivaloyloxymethyl butyrate (Pivanex, AN-9) as a single agent in refractory non-small cell lung cancer (NSCLC). Pivanex (2.34 g/m2 per day) was administered as a 6-h continuous intravenous infusion, daily for 3 days, and repeated every 21 days until disease progression. Forty-seven patients were treated. More than 90% of patients had received both a platinum compound and a taxane and 32% had received three or more prior chemotherapy regimens. The most common toxicities were transient grade 1-2 fatigue (34%), nausea (17%), and dysgeusia (11%). Three patients had partial responses (6.4 and 95%; CI 1.4-18.7%) and 14 patients had stable disease for > or =12 weeks (30%). Median survival for all patients was 6.2 months with 1-year survival of 26%. For patients who received fewer than three prior chemotherapy regimens, median survival was 7.8 months and 1-year survival was 31%. Pivanex is well tolerated and appears to be active as a single agent in patients with advanced NSCLC refractory to previous chemotherapy. Based on its therapeutic activity and favorable safety profile, further studies of Pivanex in NSCLC, particularly in combination with current chemotherapeutic agents, are warranted.

Efficacy of transcranial motor evoked potentials, mechanically elicited electromyography, and evoked electromyography to assess nerve root function during sustained compression in a porcine model.

STUDY DESIGN: This is an animal experiment using transcranial motor evoked potentials (TcMEPs), mechanically elicited electromyographic (EMG) responses, and evoked EMG responses during nerve root compression in a pig model. OBJECTIVE: To compare these 3 electrophysiological measures for compression applied to a lumbar nerve root. SUMMARY OF BACKGROUND DATA: Lumbar nerve root injury may result in motor weakness in up to 30% of spinal deformity cases. Compressive injury may occur during the surgical approach, decompression, and manipulation of the spine. Using an established porcine model, we examined the changes to TcMEPs, mechanically elicited EMG responses, and evoked EMG responses during varied compressive forces. METHODS: TcMEPs, mechanically elicited EMG responses, and evoked EMG responses were recorded for the tibialis anterior muscle in 16 experiments. Precompression TcMEP and nerve root stimulation threshold (NRT) were obtained. The dominant root was compressed at 1 N (n = 8) or 2 N (n = 8) for 10 minutes. TcMEP was recorded every minute during compression, and TcMEP and NRT were recorded after both compression and 10 minutes of recovery. RESULTS: After 10 minutes of 1-N compression, TcMEP amplitude of the tibialis anterior muscle decreased to 69% ± 13% of baseline (P < 0.02 vs. baseline). The mean NRT increased to 645% ± 433% (P < 0.02 vs. baseline NRT). After the recovery period, TcMEP in the 1-N group returned to 98% ± 11% of baseline (P = 0.36 vs. baseline). After 10 minutes of 2-N compression, TcMEPs from the tibialis anterior muscle decreased to 27% ± 15% of baseline (P < 0.02 vs. baseline). After the recovery period, TcMEP in the 2-N group returned to 30% ± 10% of baseline (P < 0.02 vs. baseline). Tonic EMG activity was observed in 3 nerve roots compressed at 2 N. CONCLUSION: Compression at 1 and 2 N produced consistent changes in TcMEPs and EMG responses. TcMEP monitoring is sensitive to an increase in compressive force. TcMEP amplitude change was correlated to the force applied and the ability of the nerve root to recover. Mechanically elicited EMG responses were not sensitive to nerve root compression. LEVEL OF EVIDENCE: N/A.

Stereotactic lesions for the treatment of psychiatric disorders.

OBJECT: The use of deep brain stimulation (DBS) has recently been expanded to the investigational treatment of specific psychiatric disorders. Much like movement disorders, the targets selected for DBS are based on past experience with stereotactic lesions. A literature review of past studies incorporating stereotactic lesions for psychiatric disorders was performed to provide historical context and possible guidance for current and future attempts at treating psychiatric disorders with DBS. METHODS: Original copies of the proceedings of the second, third, fourth, and fifth World Congresses of Psychiatric Surgery meetings were reviewed, and a Medline search was conducted for studies with the word "psychosurgery" and each of 14 highly prevalent psychiatric conditions identified by the National Institute of Mental Health. Postoperative results for 1145 patients with stereotactic brain lesions targeting various anatomical foci were standardized using a 5-point scale (3 [free of symptoms] to -1 [worse]). Each patient was entered into a database as a unique data point and used for this literature review. RESULTS: General anxiety disorder and obsessive-compulsive disorder had the greatest reported improvements from anterior capsulotomy, and bipolar disorder, depression, and schizoaffective disorder had the greatest reported improvements from anterior cingulotomy, supporting these areas for DBS investigation. Addiction and schizophrenia showed the least improvement from surgery. Therefore, pursuing the treatment of these disorders with DBS using the targets in these studies may be ineffective. CONCLUSIONS: This study provides retrospective data that suggest which anatomical focus may be effective to lesion or stimulate for the treatment of each of several psychiatric disorders.