Conservative Versus Operative Treatment of Proximal Humerus Fractures in Older Individuals­an Analysis of Insurance Data.

BACKGROUND: Little is known about the frequency and results of conservative treatment of proximal humerus fractures in older individuals. METHODS: Billing data of the BARMER health insurance carrier for all patients of age 65 and above with proximal humerus fractures in the years 2005-2021 were retrospectively analyzed with multivariable Cox regression models, taking account of the patients' age, sex, and 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 with the Bonferroni-Holm method. RESULTS: 54% of 81 909 patients 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 HR 0.89, 95% confidence interval [0,86; 0,91]) and fewer MAE (0.90; [0.88; 0.92]) and 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). 3.1% of the patients who had been initially treated conservatively underwent surgery within 6 months of their diagnosis. Risk factors for the failure of conservative treatment included alcohol abuse, obesity, cancer, diabetes mellitus, Parkinson disease, and osteoporosis. CONCLUSION: The conservative treatment of proximal humerus fracture is associated with a lower overall rate of complications due to surgery or trauma, but also with more MAE and TE and higher overall 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.

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.

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.

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%).

Predictors of Successful First-Pass Thrombectomy with a Balloon Guide Catheter: Results of a Decision Tree Analysis.

Complete recanalization after a single retrieval maneuver is an interventional goal in acute ischemic stroke and an independent factor for good clinical outcome. Anatomical biomarkers for predicting clot removal difficulties have not been comprehensively analyzed and await unused. We retrospectively evaluated 200 consecutive patients who suffered acute stroke and occlusion of the anterior circulation and were treated with mechanical thrombectomy through a balloon guide catheter (BGC). The primary objective was to evaluate the influence of carotid tortuosity and BGC positioning on the one-pass Modified Thrombolysis in Cerebral Infarction Scale (mTICI) 3 rate, and secondarily, the influence of communicating arteries on the angiographic results. After the first-pass mTICI 3, recanalization fell from 51 to 13%. The regression models and decision tree (supervised machine learning) results concurred: carotid tortuosity was the main constraint on efficacy, reducing the likelihood of mTICI 3 after one pass to 30%. BGC positioning was relevant only in carotid arteries without elongation: BGCs located in the distal internal carotid artery (ICA) had a 70% probability of complete recanalization after one pass, dropping to 43% if located in the proximal ICA. These findings demonstrate that first-pass mTICI 3 is influenced by anatomical and interventional factors capable of being anticipated, enabling the BGC technique to be adapted to patient's anatomy to enhance effectivity.

Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort.

PURPOSE: The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS: From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided into iSHH-I and iSHH-II subtypes in the HIT-2000-BIS4 cohort and a validation cohort (n = 71) from the HIT group and Russia. RESULTS: Five years after diagnosis, patients with desmoplastic medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN; n = 42) had 93% progression-free survival (5y-PFS), 100% overall survival (5y-OS), and 93% CSI-free (5y-CSI-free) survival. Patients with CMB/LCA (n = 45) had 37% 5y-PFS, 62% 5y-OS, and 39% 5y-CSI-free survival. Local radiotherapy did not improve survival in patients with CMB/LCA. All DMB/MBEN assessed by DNA methylation profiling belonged to the SHH-INF subgroup. Group 3 patients (5y-PFS, 36%; n = 14) relapsed more frequently than the SHH-INF group (5y-PFS, 93%; n = 28) or group 4 patients (5y-PFS, 83%; n = 6; P < .001). SHH-INF split into iSHH-I and iSHH-II subtypes in HIT-2000-BIS4 and the validation cohort, without prognostic impact (5y-PFS: iSHH-I, 73%, v iSHH-II, 83%; P = .25; n = 99). Intelligence quotient (IQ) was significantly lower in patients after CSI (mean IQ, 90 [no radiotherapy], v 74 [CSI]; P = .012). CONCLUSION: Systemic chemotherapy and intraventricular methotrexate led to favorable survival in both iSHH subtypes of SHH-activated DMB/MBEN with acceptable neurotoxicity. Survival in patients with non-wingless (WNT)/non-SHH disease with CMB/LCA was not improved by local radiotherapy. Patients with group 4 disease had more favorable survival rates than those with group 3 medulloblastoma.

Validation and refinement of the revised 2017 European LeukemiaNet genetic risk stratification of acute myeloid leukemia.

The revised 2017 European LeukemiaNet (ELN) recommendations for genetic risk stratification of acute myeloid leukemia have been widely adopted, but have not yet been validated in large cohorts of AML patients. We studied 1116 newly diagnosed AML patients (age range, 18-86 years) who had received induction chemotherapy. Among 771 patients not selected by genetics, the ELN-2017 classification re-assigned 26.5% of patients into a more favorable or, more commonly, a more adverse-risk group compared with the ELN-2010 recommendations. Forty percent of the cohort, and 51% of patients ≥60 years, were classified as adverse-risk by ELN-2017. In 599 patients <60 years, estimated 5-year overall survival (OS) was 64% for ELN-2017 favorable, 42% for intermediate-risk and 20% for adverse-risk patients. Among 517 patients aged ≥60 years, corresponding 5-year OS rates were 37, 16, and 6%. Patients with biallelic CEBPA mutations or inv(16) had particularly favorable outcomes, while patients with mutated TP53 and a complex karyotype had especially poor prognosis. DNMT3A mutations associated with inferior OS within each ELN-2017 risk group. Our results validate the prognostic significance of the revised ELN-2017 risk classification in AML patients receiving induction chemotherapy across a broad age range. Further refinement of the ELN-2017 risk classification is possible.

An improved one-sample log-rank test.

The one-sample log-rank test allows to compare the survival of a single sample with a prefixed reference survival curve. It naturally applies in single-arm phase IIa trials with time-to-event endpoint. Several authors have described that the original one-sample log-rank test is conservative when sample size is small and have proposed strategies to correct the conservativeness. Here, we propose an alternative approach to improve the one-sample log-rank test. Our new one-sample log-rank statistic is based on the unique transformation of the underlying counting process martingale such that the moments of the limiting normal distribution have no shared parameters. Simulation results show that the new one-sample log-rank test gives type I error rate and power close to the nominal levels also when sample size is small, while relevantly reducing the required sample size to achieve the desired power as compared to current approaches to design studies to compare the survival outcome of a sample with a reference.