Citations

Large sample sizes are required in randomized clinical trials designed to meet typical one‐sided 2.5% α‐level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two‐arm superiority trials over a 15‐year period. The design parameters examined were the α‐level and the number of trials conducted over the 15‐year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one‐sided 2.5% α‐level, performing a series of small trials with relaxed α‐levels leads on average to larger survival benefits over a 15‐year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases. Copyright © 2016 John Wiley & Sons, Ltd.

ObjectivesTo describe medium‐ to long‐term follow‐up of patients undergoing device closure of patent foramen ovale (PFO) for stroke or transient ischemic attack (TIA).BackgroundTranscatheter device closure of PFO continues to be used for secondary prevention of cryptogenic stroke or TIA, but data are lacking regarding long‐term outcomes.MethodsWe reviewed the Mayo Clinic Rochester PFO database for patients who underwent device closure of PFO for secondary prevention of stroke/TIA from December 2001 to June 2012. Demographic, clinical, procedural, and follow‐up data were reviewed. Recurrence rate of stroke/TIA were calculated. Data were analyzed to identify risk factors of recurrent neurologic events.ResultsSeven hundred and thirty patients (mean age 53 years; 40% female) were included in our study. Most patients (72%) had cryptogenic stroke as their qualifying event for PFO closure. There were no procedure‐related deaths or strokes. The most commonly used device was the Amplatzer Septal Occluder (82%). Median follow‐up was 6 years. A 3.9% of patients had documented residual right‐to‐left shunting at last echocardiogram. Recurrent stroke and/or TIA were reported in 45 patients, (6.3% of patients with follow‐up data). Patients who experienced recurrent stroke/TIA were older and had a higher rate of diabetes and hypertension than those who did not. The presence of residual shunt did not correlate with risk of recurrent events.ConclusionsDevice closure of PFO can be performed safely with very good long‐term resolution of atrial shunting. Recurrent neurologic events after PFO closure may reflect additional comorbid risk factors unrelated to the potential for paradoxical embolism. © 2016 Wiley Periodicals, Inc.

Over the past decade, a number of changes have occurred in the diagnostic evaluation, management, and long‐term follow‐up of patients with POEMS syndrome at our institution. This study included 291 patients with POEMS syndrome diagnosed at the Mayo Clinic between 1974 and 2014. Patients diagnosed after 2003 had more features of the syndrome identified at diagnosis and were more likely to receive an autologous transplant (49% versus 8%, P < 0.0001) and to have achieved a hematologic complete response (CR) to treatment (41% vs 25%, P < 0.0001). With 2273 person‐years of follow‐up, 10‐year overall survival (OS) was 62% (95% C.I., 56%, 67%). On multivariate analysis, the three factors associated with superior OS were younger age (RR 0.98 [0.96–1.00]), albumin greater‐than 3.2 g/dL (RR 0.5 [0.32–0.89]) and attainment of complete hematologic response (RR 0.4 [0.2, 0.9]). This study confirms the very good long‐term outcomes of patients with POEMS syndrome and identifies two new prognostic risk factors: albumin at diagnosis and attainment of complete hematologic response. Am. J. Hematol. 91:585–589, 2016. © 2016 Wiley Periodicals, Inc.

Objective Autologous chondrocyte implantation (ACI) has not been proven to be durable over the long-term. The purpose of this systematic review was (1) to evaluate activity level and knee function, (2) to evaluate reoperation and failure rates, and (3) to analyze risk factors for reoperation and failure of ACI at minimum long-term follow-up. Design A comprehensive review was performed for studies with long-term outcomes after ACI for cartilage defect repair. Studies reported outcome scores such as Tegner score, Lysholm score, and International Knee Documentation Society (IKDC) score along with rates of failure and reoperation. Modified Coleman Methodology Scores were calculated to assess study methodological quality. Results Nine studies with a total of 771 patients with a mean age of 33.4 ± 2.5 years, mean defect size of 5.9 ± 1.6 cm 2 , and mean follow-up of 11.4 years were included. Tegner score, Lysholm score, and IKDC score change from preoperative to final follow-up was 1.1 (95% CI 0.8-1.4, P < 0.001), 24.9 points (95% CI 18.8-31, P < 0.001), and 16.5 points (95% CI 5.4-27.5, P < 0.01), respectively. The mean failure and reoperation rates were 18% and 37%, respectively. Increased age and lesion size (>4.5 cm 2 ) were significantly correlated with increased risk of reoperation and failure. Conclusions Overall, ACI demonstrated successful outcomes in 82% of patients over the long-term. Increased patient age and lesion size greater than 4.5 cm 2 were risk factors for a higher reoperation and failure rate. Nonetheless, this review is limited by heterogeneity in surgical technique, and lesion and patient characteristics.

Objective Relationships between duplex findings and data on health-related quality of life (QoL) to assess long-term results of treatment of varicose veins and chronic venous insufficiency (CVI) are not well known. The goal of this review was to correlate duplex findings and QoL assessments in clinical studies with long-term follow-up. Methods A review of the English language literature on PUBMED revealed 17 clinical studies, including 9 randomized controlled trials (RCTs), 6 prospective, and 2 retrospective studies that included patients with at least 5-year follow-up after endovenous laser ablation (EVLA), radiofrequency ablation (RFA), ultrasound-guided foam sclerotherapy (UGFS), and traditional superficial venous surgery. Results At 5 years, great saphenous vein (GSV) occlusion rate on duplex ultrasound ranged from 66% to 82% for EVLA, from 62% to 92% for RFA, from 41% to 58% for UGFS and from 54% to 85% for surgery. Freedom from GSV reflux rates were 82% and 84%, respectively for EVLA and surgery, and ranged between 84% and 95% for RFA. Significant improvements were observed in several domains of generic QoL and in most domains of venous disease-specific QoL, irrespective of the treatment. In at least one RCT, CIVIQ scores correlated well with abnormal duplex findings in patients who underwent treatment with UGFS. In another RCT, long-term AVVQ was significantly better after surgery as compared with UGFS similar to results of duplex findings. Conclusions Analysis of the available literature confirmed that all four techniques were effective in the abolishment of reflux or obliteration of the GSV. Moreover, well-designed RCTs with large sample size are needed to produce robust long-term data on clinical outcome after treatment of varicose veins and CVI and to better understand the relationships between duplex-derived data and QoL assessments.

AbstractBlood and urine acylcarnitine profiles are commonly used to diagnose long‐chain fatty acid oxidation disorders (FAOD: i.e., long‐chain hydroxy‐acyl‐CoA dehydrogenase [LCHAD] and carnitine palmitoyltransferase 2 [CPT2] deficiency), but the global metabolic impact of long‐chain FAOD has not been reported. We utilized untargeted metabolomics to characterize plasma metabolites in 12 overnight‐fasted individuals with FAOD (10 LCHAD, two CPT2) and 11 healthy age‐, sex‐, and body mass index (BMI)‐matched controls, with the caveat that individuals with FAOD consume a low‐fat diet supplemented with medium‐chain triglycerides (MCT) while matched controls consume a typical American diet. In plasma 832 metabolites were identified, and partial least squared‐discriminant analysis (PLS‐DA) identified 114 non‐acylcarnitine variables that discriminated FAOD subjects and controls. FAOD individuals had significantly higher triglycerides and lower specific phosphatidylethanolamines, ceramides, and sphingomyelins. Differences in phosphatidylcholines were also found but the directionality differed by metabolite species. Further, there were few differences in non‐lipid metabolites, indicating the metabolic impact of FAOD specifically on lipid pathways. This analysis provides evidence that LCHAD/CPT2 deficiency significantly alters complex lipid pathway flux. This metabolic signature may provide new clinical tools capable of confirming or diagnosing FAOD, even in subjects with a mild phenotype, and may provide clues regarding the biochemical and metabolic impact of FAOD that is relevant to the etiology of FAOD symptoms.

Purpose To evaluate (1) activity level and knee function, (2) reoperation and failure rates, and (3) risk factors for reoperation and failure of osteochondral autograft transfer (OAT) at minimum long‐term follow‐up. Methods A comprehensive review was performed for long‐term outcomes after OAT. Studies reported on activity‐based outcomes (Tegner Activity Scale) and clinical outcomes (Lysholm score and International Knee Documentation Committee score). Reoperation and failure rates, as defined by the publishing authors, were recorded for each study. Modified Coleman Methodology Scores were calculated to assess study methodological quality. Results Ten studies with a total of 610 patients with an average age of 27.0 years at the time of surgery and a mean follow‐up of 10.2 years were included. The mean defect size was 2.6 cm 2 (range, 0.9 to 20.0 cm 2 ). The mean duration of symptoms before surgery was 4.8 years. From preoperative to final follow‐up, International Knee Documentation Committee scores and Lysholm scores improved significantly by 42.4 (95% confidence interval [CI], 31.8 to 53.1, P < .001) and 21.1 (95% CI, 12.2 to 30.0, P < .01), respectively. Tegner score did not improve significantly (0.76, 95% CI, −0.83 to 2.36, P = .35). Overall failure rate was 28% and reoperation rate was 19%. Increased age, previous surgery, and defect size positively correlated with increased risk of failure. Concomitant surgical procedures negatively correlated with failure rate. Conclusions Overall, OAT showed successful outcomes in 72% of patients at long‐term follow‐up. Increased age, previous surgery, and defect size correlated positively with failure rate, whereas success improved with concomitant surgical procedures. Nonetheless, this systematic review is limited by heterogeneity in a surgical technique, lesion and patient characteristics, and reporting of nonstandardized outcome measures. Level of Evidence Level IV, systematic review of Level I‐IV studies.

OBJECTIVE The purpose of this study was to report the long-term clinical outcomes following 3- and 4-level anterior cervical discectomy and fusion (ACDF). METHODS A retrospective review of all adult neurosurgical patients undergoing elective ACDF for degenerative disease at a single institution between 1996 and 2013 was performed. Patients who underwent first-time 3- or 4-level ACDF were included; patients with previous cervical spine surgery, those undergoing anterior/posterior approaches, and those with corpectomy were excluded. Outcome measures included perioperative complication rates, fusion rates, need for revision surgery, Nurick Scores, Odom's criteria, symptom resolution, neck visual analog scale (VAS) pain score, and persistent narcotics usage. RESULTS Seventy-one patients who underwent 3-level ACDF and 26 patients who underwent 4-level ACDF were identified and followed for an average of 7.6 ± 4.2 years. There was 1 case (3.9%) of deep wound infection in the 4-level group and 1 case in the 3-level group (1.4%; p = 0.454). Postoperatively, 31% of patients in the 4-level group complained of dysphagia, compared with 12.7% in the 3-level group (p = 0.038). The fusion rate was 84.6% after 4-level ACDF and 94.4% after 3-level ACDF (p = 0.122). At last follow-up, a significantly higher proportion of patients in the 4-level group continued to have axial neck pain (53.8%) than in the 3-level group (31%; p = 0.039); the daily oral morphine equivalent dose was significantly higher in the 4-level group (143 ± 97 mg/day) than in the 3-level group (25 ± 10 mg/day; p = 0.030). Outcomes based on Odom's criteria were also different between cohorts (p = 0.044), with a significantly lower proportion of patients in the 4-level ACDF group experiencing an excellent/good outcome. CONCLUSIONS In this study, patients who underwent 4-level ACDF had significantly higher rates of dysphagia, postoperative neck pain, and postoperative narcotic usage when compared with patients who underwent 3-level ACDF. Pseudarthrosis and deep wound infection rates were also higher in the 4-level group, although this did not reach statistical significance. Additionally, a smaller proportion of patients achieved a good/excellent outcome in the 4-level group than in the 3-level group. These findings suggest a significant increase of perioperative morbidity and worsened outcomes for patients who undergo 4- versus 3-level ACDF.