The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PFT).

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n=95) and Z6P3 (n=95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p=0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. This article is protected by copyright. All rights reserved.

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. INTRODUCTION This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. METHODS Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. RESULTS For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). CONCLUSIONS Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT)

Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.

Long-Term Outcome After Monosegmental L4/5 Stabilization for Degenerative Spondylolisthesis With the Dynesys Device

STUDY DESIGN:: retrospective analysis of prospectively collected clinical data. OBJECTIVE:: To assess the long-term outcome of patients with monosegmental L4/5 degenerative spondylolisthesis treated with the dynamic Dynesys device. SUMMARY OF BACKGROUND DATA:: The Dynesys® system has been used as a semirigid, lumbar dorsal pedicular stabilization device since 1994. Good short-term results have been reported, but little is known about the long-term outcome following treatment for degenerative spondylolisthesis at the L4/5 level. METHODS:: 39 consecutive patients with symptomatic degenerative lumbar spondylolisthesis at the L4/5 level were treated with bilateral decompression and Dynesys instrumentation. At a mean follow-up of 7.2 years (range 5.0-11.2▒y) they underwent clinical and radiographic evaluation and quality of life assessment. RESULTS:: At final follow-up back pain improved in 89% and leg pain improved in 86% of patients compared to preoperative status. 83% of patients reported global subjective improvement. 92% would undergo the surgery again. 8 patients (21%) required further surgery due to symptomatic adjacent segment disease (6 cases), late onset infection (1 case), and screw breakage (1 case). In 9 cases radiological progression of spondylolisthesis at the operated segment was found. 74% of operated segments showed limited flexion-extension range of less than 4°. Adjacent segment pathology, though without clinical correlation, was diagnosed at the L5/S1 (17.9%) and L3/4 (28.2%) segments. In 4 cases asymptomatic screw loosening was observed. CONCLUSION:: Monosegmental Dynesys instrumentation of degenerative spondylolisthesis at L4/5 shows good long-term results. The rate of secondary surgeries is comparable to other dorsal instrumentation devices. Residual range of motion in the stabilized segment is reduced, and the rate of radiological and symptomatic adjacent segment degeneration is low. Patient satisfaction is high. Dynesys stabilization of symptomatic L4/5 degenerative spondylolisthesis is a possible alternative to other stabilization devices.

Long-term results after proximal thoracic aortic redo surgery

Objective: To evaluate early and mid-term results in patients undergoing proximal thoracic aortic redo surgery. Methods: We analyzed 60 patients (median age 60 years, median logistic EuroSCORE 40) who underwent proximal thoracic aortic redo surgery between January 2005 and April 2012. Outcome and risk factors were analyzed. Results: In hospital mortality was 13%, perioperative neurologic injury was 7%. Fifty percent of patients underwent redo surgery in an urgent or emergency setting. In 65%, partial or total arch replacement with or without conventional or frozen elephant trunk extension was performed. The preoperative logistic EuroSCORE I confirmed to be a reliable predictor of adverse outcome- (ROC 0.786, 95%CI 0.64–0.93) as did the new EuroSCORE II model: ROC 0.882 95%CI 0.78–0.98. Extensive individual logistic EuroSCORE I levels more than 67 showed an OR of 7.01, 95%CI 1.43–34.27. A EuroSCORE II larger than 28 showed an OR of 4.44 (95%CI 1.4–14.06). Multivariate logistic regression analysis identified a critical preoperative state (OR 7.96, 95%CI 1.51–38.79) but not advanced age (OR 2.46, 95%CI 0.48–12.66) as the strongest independent predictor of in-hospital mortality. Median follow-up was 23 months (1–52 months). One year and five year actuarial survival rates were 83% and 69% respectively. Freedom from reoperation during follow-up was 100%. Conclusions: Despite a substantial early attrition rate in patients presenting with a critical preoperative state, proximal thoracic aortic redo surgery provides excellent early and mid-term results. Higher EuroSCORE I and II levels and a critical preoperative state but not advanced age are independent predictors of in-hospital mortality. As a consequence, age alone should no longer be regarded as a contraindication for surgical treatment in this particular group of patient

[Medium-term results after m. vastus medialis obliquus-plasty for lateral patellar dislocation]

Progressive retropatellar arthrosis is often seen in dated rigid distal realignment (i.e. osteotomy of tuberositas) at long-term follow-ups. Therefore, operations for lateral dislocation of the patella are still discussed controversially. Dynamic, proximal realignments seem to have lower rates of arthrosis but higher rates of redislocation. Recently, in anatomic and biomechanic studies, the m. vastus medialis obliquus (vmo) was found to be one of the most important proximal restraints to lateral dislocation of the patella.A total of 28 patients (mean age 21.5 years) were treated between 1994 and 2003 with a plasty of the vmo for lateral patellar dislocation. The technique was performed for most etiologies of femoropatellar instability.For this proximal soft tissue technique, the muscle tendon is detached from its patellar insertion. Subsequently, the tendon is reinserted at the patella 10-15 mm more distally and fixed with Mitek anchors. Full weight bearing in extension is possible immediately after surgery. An active vastus medialis training is started after 6 weeks.Of the patients, 27 were evaluated clinically and radiologically in 2004 (a mean of 5 years postoperatively). A total of 83% of the patients estimated the result to be good or excellent, 10% were satisfied and 7% were discontent. The mean Lysholm-Knee-Score was 83.1 points. Two patients suffered a patella redislocation (7%). A statistically significant improvement of the congruence angle was noted in the radiographs, even in medium-term controls. In 89% of the cases no or only little retropatellar arthrosis was observed. These 5 year results are comparable to those of other techniques for distal or proximal realignments. The rate of redislocation was below average. Compared to the rate of retropatellar arthrosis in long-term results of rigid distal realignment, our patients demonstrated a relative low rate after 5 years. We attribute this to the minimal interference in physiological joint mechanics and to the restored anatomy. In terms of future long-term results, our findings are promising. The idea of a proximal dynamic stabilization and the causal operative approach at the origin of pathology using vmo-plasty was confirmed in recent anatomic and biomechanic studies. Over or under correction of soft tissues could be adapted. More rigid techniques of distal realignment do not allow an adaptation to this extent and can lead to prearthrotic hyperpression in the medial femoropatellar and femorotibial joints.

The clinical and structural long-term results of open repair of massive tears of the rotator cuff

BACKGROUND: At a mean follow-up of 3.1 years, twenty-seven consecutive repairs of massive rotator cuff tears yielded good and excellent clinical results despite a retear rate of 37%. Patients with a retear had improvement over the preoperative state, but those with a structurally intact repair had a substantially better result. The purpose of this study was to reassess the same patients to determine the long-term functional and structural results. METHODS: At a mean follow-up interval of 9.9 years, twenty-three of the twenty-seven patients returned for a review and were examined clinically, radiographically, and with magnetic resonance imaging with use of a methodology identical to that used at 3.1 years. RESULTS: Twenty-two of the twenty-three patients remained very satisfied or satisfied with the result. The mean subjective shoulder value was 82% (compared with 80% at 3.1 years). The mean relative Constant score was 85% (compared with 83% at 3.1 years). The retear rate was 57% at 9.9 years (compared with 37% at 3.1 years; p = 0.168). Patients with an intact repair had a better result than those with a failed reconstruction with respect to the mean absolute Constant score (81 compared with 64 points, respectively; p = 0.015), mean relative Constant score (95% and 77%; p = 0.002), and mean strength of abduction (5.5 and 2.6 kg; p = 0.007). The mean retear size had increased from 882 to 1164 mm(2) (p = 0.016). Supraspinatus and infraspinatus muscle fatty infiltration had increased (p = 0.004 and 0.008, respectively). Muscles with torn tendons preoperatively showed more fatty infiltration than muscles with intact tendons preoperatively, regardless of repair integrity. Shoulders with a retear had a significantly higher mean acromion index than those without retear (0.75 and 0.65, respectively; p = 0.004). CONCLUSIONS: Open repair of massive rotator cuff tears yielded clinically durable, excellent results with high patient satisfaction at a mean of almost ten years postoperatively. Conversely, fatty muscle infiltration of the supraspinatus and infraspinatus progressed, and the retear size increased over time. The preoperative integrity of the tendon appeared to be protective against muscle deterioration. A wide lateral extension of the acromion was identified as a previously unknown risk factor for retearing.

The association between in-stent neoatherosclerosis and native coronary artery disease progression: a long-term angiographic and optical coherence tomography cohort study.

AIMS The purpose of the present study was to investigate the relationship between in-stent neoatherosclerosis (NA) and native atherosclerosis progression of untreated coronary segments. METHODS AND RESULTS In-stent NA was assessed by optical coherence tomography (OCT) among patients included in the SIRTAX-LATE OCT study 5 years after drug-eluting stent (DES) (sirolimus-eluting and paclitaxel-eluting stents) implantation. Neoatherosclerosis was defined as the presence of fibroatheroma or fibrocalcific plaque within the neointima of stented segments with a longitudinal extension >1.0 mm. Atherosclerosis progression in untreated native coronary segments was evaluated by serial quantitative coronary angiography (QCA). The change in minimal lumen diameter (MLD) was serially assessed within matched segments at baseline and 5-year angiographic follow-up. The key clinical endpoint was non-target lesion (non-TL) revascularization throughout 5 years. A total of 88 patients with 88 lesions were available for OCT analysis 5 years after DES implantation. In-stent NA was observed in 16% of lesions with the majority of plaques being fibroatheromas (11.4%) followed by fibrocalcific plaques (5.7%). A total of 704 non-TL segments were serially evaluated by QCA. Between baseline and 5-year follow-up, the reduction in MLD was significantly more pronounced in patients with NA (-0.25 mm, 95% CI -0.36 to -0.17 mm) when compared with patients without NA (-0.13 mm, 95% CI -0.17 to -0.10 mm, P = 0.002). Similarly, non-TL revascularization was more frequent in patients with NA (78.6%) when compared with patients without NA (44.6%, P = 0.028) throughout 5 years. CONCLUSIONS In-stent NA is more common among patients with angiographic and clinical evidence of native atherosclerosis progression suggesting similar pathophysiological mechanisms.SIRTAX trial is registered at http://www.clinicaltrials.gov/ct2/show/NCT00617084.

Long-term results of a prospective randomised trial assessing the impact of readaptation of the dorsolateral peritoneal layer following extended pelvic lymph node dissection and cystectomy.

OBJECTIVE To evaluate the long term oncological and functional outcomes after readaptation of the dorsolateral peritoneal layer following pelvic lymph node dissection (PLND) and cystectomy . PATIENTS AND METHODS A randomised, single-center, single-blinded, two-arm trial was conducted on 200 consecutive cystectomy patients who underwent PLND and cystectomy for bladder cancer (terms of the rate of local (pelvic) recurrence (5/95 [5.3%] in group A; 7/93 [7.5%] in group B; p = 0.53), the rate of distant metastases (21/95 [22.1%] in group A; 23/93 [24.7%] in group B; p = 0.67), cancer-specific survival (p = 0.37), and overall survival (p = 0.59). Group A had significantly better bowel function at 3 (p < 0.001), 6 (p < 0.006), 12 (p <0.006) and 24 months (p = 0.04), and significantly less postoperative abdominal pain and bloating at 3 (p = 0.002) and 6 months (p = 0.01). CONCLUSION Readaptation of the dorsolateral peritoneal layer following PLND and cystectomy has a beneficial long-term impact on bowel function and postoperative pain without compromising oncological radicality. This article is protected by copyright. All rights reserved.

Long-term fluid circulation in extensional faults in the central Catalan Coastal Ranges: P-T constraints from neoformed chlorite and K-white mica

The neoformation of chlorite and K-white mica in fault rocks from two main faults of the central Catalan Coastal Ranges, the Vallès and the Hospital faults, has allowed us to constrain the P–T conditions during fault evolution using thermodynamic modeling. Crystallization of M1 and M2 muscovite and microcline occured as result of deuteric alteration during the exhumation of the pluton (290 °C > T > 370 °C) in the Permian. After that, three tectonic events have been distinguished. The first tectonic event, attributed to the Mesozoic rifting, is characterized by precipitation of M3 and M4 phengite together with chlorite and calcite C1 at temperatures between 190 and 310 °C. The second tectonic event attributed to the Paleogene compression has only been identified in the Hospital fault with precipitation of low-temperature calcite C2. The shortcut produced during inversion of the Vallès fault was probably the responsible for the lack of neoformed minerals within this fault. Finally, the third tectonic event, which is related to the Neogene extension, is characterized in the Vallès fault by a new generation of chlorite, associated with calcite C4 and laumontite, formed at temperatures between 125 and 190 °C in the absence of K-white mica. Differently, the Hospital fault is characterized by the precipitation of calcite C3 during the syn-rift stage at temperatures around 150 °C and by low-temperature fluids precipitating calcites C5, C6 and PC1 during the post-rift stage. During the two extensional events (Mesozoic and Neogene), faults acted as conduits for hot fluids producing anomalous high geothermal gradients (50 °C/km minimum).

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study

UNLABELLED The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. INTRODUCTION This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. METHODS Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. RESULTS Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. CONCLUSIONS Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.

Cause-Specific Long-Term Mortality in Survivors of Childhood Cancer in Switzerland: A Population Based Study.

Survivors of childhood cancer have a higher mortality than the general population. We describe cause-specific long-term mortality in a population-based cohort of childhood cancer survivors. We included all children diagnosed with cancer in Switzerland (1976-2007) at age 0-14 years, who survived ≥5 years after diagnosis and followed survivors until December 31, 2012. We obtained causes of death (COD) from the Swiss mortality statistics and used data from the Swiss general population to calculate age-, calendar year- and sex-standardized mortality ratios (SMR), and absolute excess risks (AER) for different COD, by Poisson regression. We included 3'965 survivors and 49'704 person years at risk. Of these, 246 (6.2%) died, which was 11 times higher than expected (SMR 11.0). Mortality was particularly high for diseases of the respiratory (SMR 14.8) and circulatory system (SMR 12.7), and for second cancers (SMR 11.6). The pattern of cause-specific mortality differed by primary cancer diagnosis, and changed with time since diagnosis. In the first 10 years after 5-year survival, 78.9% of excess deaths were caused by recurrence of the original cancer (AER 46.1). Twenty-five years after diagnosis, only 36.5% (AER 9.1) were caused by recurrence, 21.3% by second cancers (AER 5.3) and 33.3% by circulatory diseases (AER 8.3). Our study confirms an elevated mortality in survivors of childhood cancer for at least 30 years after diagnosis with an increased proportion of deaths caused by late toxicities of the treatment. The results underline the importance of clinical follow-up continuing years after the end of treatment for childhood cancer. This article is protected by copyright. All rights reserved.

Long-term Outcome After Monosegmental L4/5 Stabilization for Degenerative Spondylolisthesis With the Dynesys Device.

STUDY DESIGN Retrospective analysis of prospectively collected clinical data. OBJECTIVE To assess the long-term outcome of patients with monosegmental L4/5 degenerative spondylolisthesis treated with the dynamic Dynesys device. SUMMARY OF BACKGROUND DATA The Dynesys system has been used as a semirigid, lumbar dorsal pedicular stabilization device since 1994. Good short-term results have been reported, but little is known about the long-term outcome after treatment for degenerative spondylolisthesis at the L4/5 level. METHODS A total of 39 consecutive patients with symptomatic degenerative lumbar spondylolisthesis at the L4/5 level were treated with bilateral decompression and Dynesys instrumentation. At a mean follow-up of 7.2 years (range, 5.0-11.2 y), they underwent clinical and radiographic evaluation and quality of life assessment. RESULTS At final follow-up, back pain improved in 89% and leg pain improved in 86% of patients compared with preoperative status. Eighty-three percent of patients reported global subjective improvement. Ninety-two percent would undergo the surgery again. Eight patients (21%) required further surgery because of symptomatic adjacent segment disease (6 cases), late-onset infection (1 case), and screw breakage (1 case). In 9 cases, radiologic progression of spondylolisthesis at the operated segment was found. Seventy-four percent of operated segments showed limited flexion-extension range of <4 degrees. Adjacent segment pathology, although without clinical correlation, was diagnosed at the L5/S1 (17.9%) and L3/4 (28.2%) segments. In 4 cases, asymptomatic screw loosening was observed. CONCLUSIONS Monosegmental Dynesys instrumentation of degenerative spondylolisthesis at L4/5 shows good long-term results. The rate of secondary surgeries is comparable to other dorsal instrumentation devices. Residual range of motion in the stabilized segment is reduced, and the rate of radiologic and symptomatic adjacent segment degeneration is low. Patient satisfaction is high. Dynesys stabilization of symptomatic L4/5 degenerative spondylolisthesis is a possible alternative to other stabilization devices.

How much Entrepreneurial Orientation (EO) is needed for Long-term Success?

According to the STEP research framework, entrepreneurial orientation (EO) is one key element of transgenerational value creation. EO refers to key entrepreneurial processes in a company, i.e. to the methods, practices and decision-making styles managers use to act entrepreneurially. 3 EO consists of five main dimensions and several sub dimensions. However, there is a puzzle. Many studies suggest that the higher EO, the more successful a company is. But this seems not always to be true. Just think of many of the dot.com firms at the end of the 1990s. Firm members could act very autonomously, the companies were very innovative, took high risks, were very proactive and very aggressive in the market. However, most of them were not able to survive for more than a few years. So how entrepreneurial has a firm to be in order to achieve long-term success?