Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis.

BACKGROUND: Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials. METHODS: Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding. RESULTS: Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p < 0.001) but not for dabigatran (p = 0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p < 0.001) and 13.0% for dabigatran versus 12.8% for VKA (p = 0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort. CONCLUSIONS: In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.

Two-sample survival tests based on control arm summary statistics.

The one-sample log-rank test is the preferred method for analysing the outcome of single-arm survival trials. It compares the survival distribution of patients with a prefixed reference survival curve that usually represents the expected outcome under standard of care. However, classical one-sample log-rank tests assume that the reference curve is known, ignoring that it is frequently estimated from historical data and therefore susceptible to sampling error. Neglecting the variability of the reference curve can lead to an inflated type I error rate, as shown in a previous paper. Here, we propose a new survival test that allows to account for the sampling error of the reference curve without knowledge of the full underlying historical survival time data. Our new test allows to perform a valid historical comparison of patient survival times when only a historical survival curve rather than the full historic data is available. It thus applies in settings where the two-sample log-rank test is not applicable as method of choice due to non-availability of historic individual patient survival time data. We develop sample size calculation formulas, give an example application and study the performance of the new test in a simulation study.

Making acute ischemic stroke thrombi visible in MRI imaging.

Knowledge of thrombus behavior and visualization on MRI in acute ischemic stroke is less than optimal. However, MRI sequences could be enhanced based on the typical T1 and T2 relaxation times of the target tissues, which mainly determine their signal intensities on imaging. We studied the relaxation times of a broad spectrum of clot analogs along with their image characteristics of three sequences analyzed: a T1-weighted turbo inversion-recovery sequence (T1w Turbo IR), a T1-weighted turbo spin echo with fat suppression (T1w TSE SPIR), and a T2-weighted 3D TSE with magnetization refocusing to remove T1 dependence (T2w TSE DRIVE). We compared their imaging behavior with the intensity values of normal brain tissue using the same imaging protocols as for clots. Each histological and biochemical clot component contributed to each of the relaxation times. Overall, histological composition correlated strongly with T1 times, and iron content, specifically, with T2 relaxation time. Using decision trees, fibrin content was selected as the primary biomarker for T1 relaxation times, inducing an increase. Up to four clot subgroups could be defined based on its distinctive T1 relaxation time. Clot signal intensity in the T1 and T2-weighted images varied significantly according to T1 and T2 relaxation times. Moreover, in comparison with normal brain tissue intensity values, T2w DRIVE images depict thrombi according to the principle of the more fibrin, the higher the intensity, and in T1w TSE, the more erythrocytes, the higher the intensity. These findings could facilitate improvements in MRI sequences for clot visualization and indicate that T2w DRIVE and T1w TSE sequences should depict the vast majority of acute ischemic stroke thrombi as more hyperintense than surrounding tissues.

Exploring the relationship between embolic acute stroke distribution and supra-aortic vessel patency: key findings from an in vitro model study.

BACKGROUND: We investigated differences in intracranial embolus distribution through communicating arteries in relation to supra-aortic vessel (SAV) patency. METHODS: For this experimental analysis, we created a silicone model of the extracranial and intracranial circulations using a blood-mimicking fluid under physiological pulsatile flow. We examined the sequence of embolus lodgment on injecting 104 frangible clot analogues (406 emboli) through the right internal carotid artery (CA) as SAV patency changed: (a) all SAV patent (baseline), (b) emboli from a CA occlusion, (c) emboli contralateral to a CA occlusion and (d) occlusion of the posterior circulation. The statistical analysis included a descriptive analysis of thrombi location after occlusion (absolute and relative frequencies). Sequences of occlusions were displayed in Sankey flow charts for the four SAV conditions. Associations between SAV conditions and occlusion location were tested by Fisher's exact test. Two-sided p values were compared with a significance level of 0.05. RESULTS: The total number of emboli was 406 (median fragments/clot: 4 (IQR: 3-5)). Embolus lodgment was dependent on SAV patency (p<0.0001). In all scenarios, embolism lodging in the anterior cerebral artery (ACA) occurred after a previous middle cerebral artery (MCA) embolism (MCA first lodge: 96%, 100/104). The rate of ipsilateral ACA embolism was 28.9% (28/97) at baseline, decreasing significantly when emboli originated from an occluded CA (16%, 14/88). There were more bihemispheric embolisations in cases of contralateral CA occlusion (37%, 45/122), with bilateral ACA embolisms preceding contralateral MCA embolism in 56% of cases (14/25 opposite MCA and ACA embolism). CONCLUSIONS: All emboli in the ACA occurred after a previous ipsilateral MCA embolism. Bihemispheric embolisms were rare, except when there was a coexisting occlusion in either CA, particularly in cases of a contralateral CA occlusion.

Conservative Versus Operative Treatment of Proximal Humerus Fractures in Older Individuals.

BACKGROUND: Little is known about the frequency and results of conservative treatment of proximal humerus fractures (PHF) in older individuals. METHODS: Billing data of the BARMER health insurance carrier for all patients of age ≥ 65 for the years 2005-2021 were retrospectively analyzed with multivariable Cox regression models, taking account of the patients' age, sex, and individual comorbidity profiles. The defined primary endpoints were overall survival (OS), major adverse events (MAE), thromboembolic events (TE), and complications of surgery or of trauma. Multivariable p-values for the effect of treatment on all primary endpoints were jointly adjusted using the Bonferroni-Holm method. RESULTS: Of 81 909 patients, 54% were treated conservatively. Conservative treatment was more common in those who received their diagnosis as outpatients (79.5%, vs. 37.2% for inpatients). Operative treatment was associated with significantly longer overall survival (long-term hazard ratio [HR] 0.89, 95% confidence interval [0.86; 0.91]), fewer MAE (0.90 [0.88; 0.92]), and fewer TE (0.89 [0.87; 0.92]), but more complications due to surgery or trauma (1.66 [1,.4; 1.78]; all p < 0.001). By 6 months after diagnosis, 3.1% of the patients who were initially treated conservatively had undergone surgery. Risk factors for failure of conservative treatment were alcohol abuse, obesity, cancer, diabetes mellitus, Parkinson disease, and osteoporosis. CONCLUSION: The conservative treatment of PHF is associated with a lower overall rate of complications due to surgery or trauma, but also with more MAE, more TE, and higher mortality. These findings underline the need for individualized and risk-adjusted treatment recommendations.

Robustness of apparent diffusion coefficient-based lymph node classification for diagnosis of prostate cancer metastasis.

OBJECTIVES: The aim of this proof-of-principle study combining data analysis and computer simulation was to evaluate the robustness of apparent diffusion coefficient (ADC) values for lymph node classification in prostate cancer under conditions comparable to clinical practice. MATERIALS AND METHODS: To assess differences in ADC and inter-rater variability, ADC values of 359 lymph nodes in 101 patients undergoing simultaneous prostate-specific membrane antigen (PSMA)-PET/MRI were retrospectively measured by two blinded readers and compared in a node-by-node analysis with respect to lymph node status. In addition, a phantom and 13 patients with 86 lymph nodes were prospectively measured on two different MRI scanners to analyze inter-scanner agreement. To estimate the diagnostic quality of the ADC in real-world application, a computer simulation was used to emulate the blurring caused by scanner and reader variability. To account for intra-individual correlation, the statistical analyses and simulations were based on linear mixed models. RESULTS: The mean ADC of lymph nodes showing PSMA signals in PET was markedly lower (0.77 × 10-3 mm2/s) compared to inconspicuous nodes (1.46 × 10-3 mm2/s, p < 0.001). High inter-reader agreement was observed for ADC measurements (ICC 0.93, 95%CI [0.92, 0.95]). Good inter-scanner agreement was observed in the phantom study and confirmed in vivo (ICC 0.89, 95%CI [0.84, 0.93]). With a median AUC of 0.95 (95%CI [0.92, 0.97]), the simulation study confirmed the diagnostic potential of ADC for lymph node classification in prostate cancer. CONCLUSION: Our model-based simulation approach implicates a high potential of ADC for lymph node classification in prostate cancer, even when inter-rater and inter-scanner variability are considered. CLINICAL RELEVANCE STATEMENT: The ADC value shows a high diagnostic potential for lymph node classification in prostate cancer. The robustness to scanner and reader variability implicates that this easy to measure and widely available method could be readily integrated into clinical routine. KEY POINTS: • The diagnostic value of the apparent diffusion coefficient (ADC) for lymph node classification in prostate cancer is unclear in the light of inter-rater and inter-scanner variability. • Metastatic and inconspicuous lymph nodes differ significantly in ADC, resulting in a high diagnostic potential that is robust to inter-scanner and inter-rater variability. • ADC has a high potential for lymph node classification in prostate cancer that is maintained under conditions comparable to clinical practice.

Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial.

PURPOSE: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS). PATIENTS AND METHODS: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method. RESULTS: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003). CONCLUSIONS: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL.

Effects of anti-osteoporosis therapy on the risk of secondary fractures and surgical complications following surgical fixation of proximal humerus fracture in older people.

BACKGROUND: age-related fragility fractures cause significant burden of disease. Within an ageing society, fracture and complication prevention will be essential to balance health expenditure growth. OBJECTIVE: to assess the effect of anti-osteoporotic therapy on surgical complications and secondary fractures after treatment of fragility fractures. PATIENTS AND METHODS: retrospective health insurance data from January 2008 to December 2019 of patients ≥65 years with proximal humeral fracture (PHF) treated using locked plate fixation (LPF) or reverse total shoulder arthroplasty were analysed. Cumulative incidences were calculated by Aalen-Johansen estimates. The influence of osteoporosis and pharmaceutical therapy on secondary fractures and surgical complications were analysed using multivariable Fine and Gray Cox regression models. RESULTS: a total of 43,310 patients (median age 79 years, 84.4% female) with a median follow-up of 40.9 months were included. Five years after PHF, 33.4% of the patients were newly diagnosed with osteoporosis and only 19.8% received anti-osteoporotic therapy. A total of 20.6% (20.1-21.1%) of the patients had at least one secondary fracture with a significant reduction of secondary fracture risk by anti-osteoporotic therapy (P < 0.001). An increased risk for surgical complications (hazard ratio: 1.35, 95% confidence interval: 1.25-1.47, P < 0.001) after LPF could be reversed by anti-osteoporotic therapy. While anti-osteoporotic therapy was more often used in female patients (35.3 vs 19.1%), male patients showed significantly stronger effects reducing the secondary fracture and surgical complication risk. CONCLUSIONS: a significant number of secondary fractures and surgical complications could be prevented by consequent osteoporosis diagnosis and treatment particularly in male patients. Health-politics and legislation must enforce guideline-based anti-osteoporotic therapy to mitigate burden of disease.

Treatment Reality of Proximal Humeral Fractures in the Elderly-Trending Variants of Locking Plate Fixation in Germany.

BACKGROUND: The surgical treatment of proximal humeral fractures (PHFs) with locking plate fixation (LPF) in the elderly is associated with high complication rates, especially in osteoporotic bone. Variants of LPF such as additional cerclages, double plating, bone grafting and cement augmentation can be applied. The objective of the study was to describe the extent of their actual use and how this changed over time. METHODS: Retrospective analysis of health claims data of the Federal Association of the Local Health Insurance Funds was performed, covering all patients aged 65 years and older, who had a coded diagnosis of PHF and were treated with LPF between 2010 and 2018. Differences between treatment variants were analyzed (explorative) via chi-squared or Kruskal-Wallis tests. RESULTS: Of the 41,216 treated patients, 32,952 (80%) were treated with LPF only, 5572 (14%) received additional screws or plates, 1983 (5%) received additional augmentations and 709 (2%) received a combination of both. During the study period, relative changes were observed as follows: -35% for LPF only, +58% for LPF with additional fracture fixation and +25% for LPF with additional augmentation. Overall, the intra-hospital complication rate was 15% with differences between the treatment variants (LPF only 15%, LPF with additional fracture fixation 14%, LPF with additional augmentation 19%; p < 0.001), and a 30-day mortality of 2%. CONCLUSIONS: Within an overall decrease of LPF by approximately one-third, there is both an absolute and relative increase of treatment variants. Collectively, they account for 20% of all coded LPFs, which might indicate more personalized treatment pathways. The leading variant was additional fracture fixation using cerclages.

Increased complication rates of salvage reverse total shoulder arthroplasty (RTSA) after failed locked plate fixation compared with primary RTSA in the treatment of proximal humeral fractures in elderly patients.

HYPOTHESIS: Common surgical treatment options for proximal humeral fractures in elderly patients include locked plate fixation (LPF) and reverse total shoulder arthroplasty (RTSA). It was hypothesized that secondary RTSA after LPF would be associated with higher complication rates and costs compared with primary RTSA. METHODS: We analyzed the health insurance data of patients aged ≥65 years who received RTSA for the treatment of a proximal humeral fracture between January 2013 and September 2019 with a pre-study phase of 5 years. Multivariable Cox, logistic, and linear regression models were used to evaluate the association between treatment group and complications, hospital length of stay, charges, and mortality rate during a 34-month follow-up period. RESULTS: A total of 14,220 patients underwent primary RTSA and 1282 patients underwent secondary RTSA after prior surgery using LPF for the treatment of proximal humeral fractures. After adjustment for patient characteristics, more surgical complications were observed after secondary RTSA during index hospitalization (odds ratio, 4.62; 95% confidence interval [CI], 4.00-5.34; P < .001) and long-term follow-up (hazard ratio, 1.52; 95% CI, 1.27-1.81; P < .001). Moreover, secondary RTSA was associated with an increased cumulative total cost of €6638.1 (95% CI, €6229.9-€7046.5; P < .001). If conversion from LPF to secondary RTSA occurred during index hospitalization, more major adverse events, more thromboembolic events, and a higher mortality rate were found in the short and long term (all P < .05). CONCLUSION: Secondary RTSA is associated with higher total costs and more complications. Hence, if surgical treatment of a proximal humeral fracture in an elderly patient is needed, prognostic factors for LPF need to be evaluated carefully. If in doubt, the surgeon should opt to perform primary RTSA as patients will benefit in the long term.

Reference curve sampling variability in one-sample log-rank tests.

The one-sample log-rank test is the method of choice for single-arm Phase II trials with time-to-event endpoint. It allows to compare the survival of patients to a reference survival curve that typically represents the expected survival under standard of care. The one-sample log-rank test, however, assumes that the reference survival curve is known. This ignores that the reference curve is commonly estimated from historic data and thus prone to sampling error. Ignoring sampling variability of the reference curve results in type I error rate inflation. We study this inflation in type I error rate analytically and by simulation. Moreover we derive the actual distribution of the one-sample log-rank test statistic, when the sampling variability of the reference curve is taken into account. In particular, we provide a consistent estimate of the factor by which the true variance of the one-sample log-rank statistic is underestimated when reference curve sampling variability is ignored. Our results are further substantiated by a case study using a real world data example in which we demonstrate how to estimate the error rate inflation in the planning stage of a trial.

High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma.

PURPOSE: Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS: Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS: Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION: In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Confirmatory adaptive group sequential designs for single-arm phase II studies with multiple time-to-event endpoints.

Existing methods concerning the assessment of long-term survival outcomes in one-armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one-sample tests for testing hypotheses on the multivariate survival distribution derived from multi-state models, while making provision for data-dependent design modifications based on all involved time-to-event endpoints. We explicitly elaborate application of the methodology to one-sample tests for the joint distribution of (i) progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi-state model for non-small cell lung cancer is used to illustrate the adaptive procedure.

Local and Systemic Therapy of Recurrent Medulloblastomas in Children and Adolescents: Results of the P-HIT-REZ 2005 Study.

Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9-16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7-10.0) and 18.5 months (CI: 13.6-23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients' survival.

The Surgical Treatment of Proximal Humeral Fractures in Elderly Patients.

BACKGROUND: The goal of this study is to compare mortality, major adverse events, and complication rates after the surgical treatment of proximal humeral fractures with locked plate fixation (LPF) versus reverse total shoulder arthroplasty (RTSA) in elderly patients. METHODS: Health insurance data from patients aged 65 and above for the period January 2010 to September 2018 were retrospectively evaluated. The median follow-up duration after LPF (40 419 patients) or RTSA (13 552 patients) was 52 months. Hazard ratios adapted to the patients' risk profiles were determined with the aid of multivariable Cox regression models. The p-values were adjusted using the Bonferroni-Holm method. RESULTS: After adaptation to the patients' risk profiles, reverse shoulder replacement showed statistically significantly lower mortality (HR 0.92, 95% confidence interval [0.88; 0.95]; p <0.001) and fewer major adverse events (HR 0.92 [0.89; 0.95]; p<0.001). Eight years after surgery, the risk of surgical complications was twice as high for LPF (12.2% [11.9; 12.7]; HR for RTSA versus LPF 0.5 [0.46; 0.55]; p<0.001 for both), with 3.8% [3.6; 4.0] of the patients receiving a secondary RTSA. Surgical complications were more common (p<0.05) in patients with a diagnosis of osteo - porosis, obesity, alcohol abuse, chronic polyarthritis, or frozen shoulder. CONCLUSION: The long-term findings are in agreement with clinical short-term findings from other studies and support the current trend toward more liberal use of reverse shoulder replacements in elderly patients.

Adaptive group sequential survival comparisons based on log-rank and pointwise test statistics.

Whereas the theory of confirmatory adaptive designs is well understood for uncensored data, implementation of adaptive designs in the context of survival trials remains challenging. Commonly used adaptive survival tests are based on the independent increments structure of the log-rank statistic. This implies some relevant limitations: On the one hand, essentially only the interim log-rank statistic may be used for design modifications (such as data-dependent sample size recalculation). Furthermore, the treatment arm allocation ratio in these classical methods is assumed to be constant throughout the trial period. Here, we propose an extension of the independent increments approach to adaptive survival tests that addresses some of these limitations. We present a confirmatory adaptive two-sample log-rank test that allows rejection regions and sample size recalculation rules to be based not only on the interim log-rank statistic, but also on point-wise survival rate estimates, simultaneously. In addition, the possibility is opened to adapt the treatment arm allocation ratio after each interim analysis in a data-dependent way. The ability to include point-wise survival rate estimators in the rejection region of a test for comparing survival curves might be attractive, e.g., for seamless phase II/III designs. Data-dependent adaptation of the allocation ratio could be helpful in multi-arm trials in order to successively steer recruitment into the study arms with the greatest chances of success. The methodology is motivated by the LOGGIC Europe Trial from pediatric oncology. Distributional properties are derived using martingale techniques in the large sample limit. Small sample properties are studied by simulation.

[Influence of complications and comorbidities on length of hospital stay and costs for surgical treatment of proximal humeral fractures]. / Einfluss von Komplikationen und Komorbiditäten auf Liegedauer und Kosten bei der operativen Behandlung der proximalen Humerusfraktur.

After a proximal humeral fracture in older patients, locked plate fixation and reverse total shoulder arthroplasty are two competing surgical procedures. Even if recent clinical studies indicate a functional superiority of reverse shoulder arthroplasty over locked plate fixation, health-economic comparative data are lacking in the literature. Health claims data of 55,070 patients aged 65 years or older who were treated with reverse total shoulder arthroplasty or locked plate fixation after proximal humeral fractures, were analyzed regarding length of hospital stay and costs. Multivariable linear regression models were used to analyze the influence of comorbidities and complications on the length of hospital stay and costs. The length of hospital stay after reverse total shoulder arthroplasty with 20.0 days (±13.5 days) was statistically noticeable longer compared to locked plate fixation with 14.6 days (±11.4 days, p < 0.001). The costs per case showed a clear difference with 11,165.70€ (±5884.36€) for reverse total shoulder arthroplasty and 7030.11€ (±5532.02€) for locked plate fixation (p < 0.001). Statistically noticeable cost increases due to comorbidities and complications underline the urgent need for specialized geriatric trauma centers.

Male Sex Is Associated with Higher Mortality and Increased Risk for Complications after Surgical Treatment of Proximal Humeral Fractures.

AIMS: The best surgical treatment of multi-fragmentary proximal humeral fractures in the elderly is a highly controversial topic. The aim of this study is to assess for sex-related differences regarding mortality and complications after reverse total shoulder arthroplasty (RTSA) and locking plate fixation (LPF). PATIENTS AND METHODS: All patients from the largest German healthcare insurance (26.5 million policy holders) above the age of 65 years that were treated with LPF or RTSA after a multi-fragmentary proximal humerus fracture between January 2010 and September 2018 were included. Multivariable Cox regression models were used to assess the association of sex with overall survival, major adverse events and surgical complications. RESULTS: A total of 8264 (15%) men and 45,707 (85%) women were followed up for a median time of 52 months. After 8 years, male patients showed significantly higher rates for death (65.8%; 95% CI 63.9-67.5% vs. 51.1%; 95% CI 50.3-51.9%; p < 0.001) and major adverse events (75.5%; 95% CI 73.8-77.1% vs. 61.7%; 95% CI 60.9-62.5%; p < 0.001). With regard to surgical complications, after adjustment of patient risk profiles, there were no differences between females and males after LPF (p > 0.05), whereas men showed a significantly increased risk after RTSA (HR 1.86; 95% CI 1.56-2.22; p < 0.001) with more revision surgeries performed (HR 1.76, 95% CI 1.46-2.12; p < 0.001) compared to women. CONCLUSION: The male sex is an independent risk factor for death and major adverse events after both LPF and RTSA. An increased risk for surgical complications after RTSA suggests that male patients benefit more from LPF. Sex should be considered before making treatment decisions.

In-hospital Complications Are More Likely to Occur After Reverse Shoulder Arthroplasty Than After Locked Plating for Proximal Humeral Fractures.

BACKGROUND: Currently, there seems to be a paradigm change in the surgical treatment of proximal humeral fractures in patients aged 65 years and older, with a considerable increase in the use of reverse total shoulder arthroplasty (RTSA) compared with angular stable internal fixation (locking plate fixation). However, even among shoulder specialists there is controversy regarding the best treatment strategy. QUESTIONS/PURPOSES: To evaluate for (1) a greater risk of in-hospital major adverse events, (2) a greater risk for in-hospital surgical complications, and (3) a greater risk of 30-day mortality, locking plate fixation and RTSA were compared for the treatment of proximal humerus fractures of patients aged 65 years and older after controlling for potentially confounding variables in a large-database analysis. METHODS: Health claims data of the largest German insurance company including approximately one-third of the population (26.5 million policyholders) between 2010 and 2018 were analyzed. This database was chosen because of its size, nationwide distribution, and high quality/completeness. In total, 55,070 patients (≥ 65 years of age) treated with locking plate fixation (75% [41,216]) or RTSA (25% [13,854]) for proximal humeral fracture were compared. As primary endpoints, major adverse events (including acute myocardial infarction, stroke, organ failure, resuscitation, and death) and surgical complications (infection, hematoma, loss of reduction, dislocation, and revision surgery) were analyzed. The risk of all endpoints was analyzed with multivariable logistic regression models in the context of comorbidities to address existing group differences. RESULTS: After controlling for potentially confounding variables such as age, sex, and risk profile, RTSA was associated with a higher risk for major adverse events (OR 1.40 [95% CI 1.29 to 1.53]; p < 0.001) and surgical complications (OR 1.13 [95% CI 1.05 to 1.21]; p < 0.01) compared with locking plate fixation. There was no evidence for an increase in mortality (OR 0.98 [95% CI 0.86 to 1.12]; p = 0.81). CONCLUSION: The increased in-hospital risk for major adverse events and surgical complications may moderate the enthusiasm associated with RTSA for proximal humeral fractures in patients 65 years and older. Treatment decisions should be based on individual risk estimation to avoid potential harmful events. Future studies must include long-term outcomes and quality of life to enlighten these findings in a broader context. LEVEL OF EVIDENCE: Level III, therapeutic study.

Local and systemic therapy of recurrent ependymoma in children and adolescents: short- and long-term results of the E-HIT-REZ 2005 study.

BACKGROUND: Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results. METHODS: Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas. RESULTS: Fifty-three patients with a median age of 6.9 years (1.25-25.4) at first recurrence and a median follow-up time of 36 months (2-115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9-120.1) vs. 95 (CI: 20.7-169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7-31.3) vs. 7 (CI: 0-15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%. CONCLUSION: The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%).