Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany.

Closed and open grade I and II tibial shaft fractures treated by reamed intramedullary nailing.

OBJECTIVE: To evaluate the results of closed and open grade I and II tibial shaft fractures treated by reamed nail and unreamed nailing. SUBJECTS AND METHODS: Between 1997 and 2000, 119 patients with tibial shaft fractures were treated with reamed tibial nails. Postoperatively 96 patients (70 closed and 26 grade I and II open fractures) were followed clinically and radiologically for up to 18 months. The nail was inserted either by patellar tendon splitting or by nonsplitting technique. The nail was inserted after overreaming by 1.5 mm. Postoperatively, patients with isolated tibial fracture were mobilized by permitting partial weight bearing on the injured leg for 6 weeks. Patients with associated ankle fractures were allowed to walk with a Sarmiento cast. RESULTS: Postoperatively, 6 (6.3%) patients developed a compartment syndrome after surgery. In 48 (50%) cases, dynamization of the nail was carried out after a mean period of 12 weeks for delayed union. Overall, a 90.6% union was obtained at a mean of 24 weeks without difference between closed or open fractures. Two (2.1%) patients with an open grade II fracture developed a deep infection requiring treatment. A 9.4% rate of malunion was observed. Eight (8.3%) patients developed screw failure without clinical consequences. At the last follow-up, 52% of patients with patellar tendon splitting had anterior knee pain, compared to those (14%) who did not have tendon splitting. CONCLUSION: Reamed intramedullary nail is a suitable implant in treating closed as well as grade I and II open tibial shaft fractures.

Endovascular aortic repair versus open surgical repair for descending thoracic aortic disease a systematic review and meta-analysis of comparative studies.

OBJECTIVES: The purpose of this study was to determine whether thoracic endovascular aortic repair (TEVAR) reduces death and morbidity compared with open surgical repair for descending thoracic aortic disease. BACKGROUND: The role of TEVAR versus open surgery remains unclear. Metaregression can be used to maximally inform adoption of new technologies by utilizing evidence from existing trials. METHODS: Data from comparative studies of TEVAR versus open repair of the descending aorta were combined through meta-analysis. Metaregression was performed to account for baseline risk factor imbalances, study design, and thoracic pathology. Due to significant heterogeneity, registry data were analyzed separately from comparative studies. RESULTS: Forty-two nonrandomized studies involving 5,888 patients were included (38 comparative studies, 4 registries). Patient characteristics were balanced except for age, as TEVAR patients were usually older than open surgery patients (p = 0.001). Registry data suggested overall perioperative complications were reduced. In comparative studies, all-cause mortality at 30 days (odds ratio [OR]: 0.44, 95% confidence interval [CI]: 0.33 to 0.59) and paraplegia (OR: 0.42, 95% CI: 0.28 to 0.63) were reduced for TEVAR versus open surgery. In addition, cardiac complications, transfusions, reoperation for bleeding, renal dysfunction, pneumonia, and length of stay were reduced. There was no significant difference in stroke, myocardial infarction, aortic reintervention, and mortality beyond 1 year. Metaregression to adjust for age imbalance, study design, and pathology did not materially change the results. CONCLUSIONS: Current data from nonrandomized studies suggest that TEVAR may reduce early death, paraplegia, renal insufficiency, transfusions, reoperation for bleeding, cardiac complications, pneumonia, and length of stay compared with open surgery. Sustained benefits on survival have not been proven.

Open elbow arthrolysis for posttraumatic elbow stiffness.

OBJECTIVES: The elbow joint is vulnerable to stiffness, especially after trauma. The aim of this study was to evaluate the results of open arthrolysis for posttraumatic elbow stiffness. DESIGN: Cohort retrospective study. PATIENTS: Eighteen consecutive patients were evaluated by an independent observer at an average of 16 months (6 to 43) after open elbow arthrolysis was performed for posttraumatic stiffness. Initial traumas were: isolated fractures (11) or dislocation (1) and complex fracture-dislocations (6). Initial treatments were: nonoperative (3), radial head resection (1), and ORIF (14). Patients presented predominantly with mixed contractures (combined extrinsic and intrinsic contractures). INTERVENTION: Open elbow arthrolysis. MAIN OUTCOME MEASUREMENTS: Elbow function and patient satisfaction were the principal outcome measures. At follow-up European Society for Shoulder and Elbow Surgery (SECEC) elbow scores were calculated. RESULTS AND CONCLUSIONS: Three patients had minor postoperative complications: 1 partial wound dehiscence, 1 subcutaneous infection, and one seroma. None of these complications influenced the final result clinically. The mean total increase in range of motion was 40 degrees (13 to 112 degrees), with a mean gain in flexion of 14 degrees (0 to 45 degrees) and 26 degrees in extension (5 to 67 degrees). No patient showed signs of elbow instability. There was no radiographic evidence of osteoarthritis progression at follow-up. We did not find any correlations between the type of stiffness, the approaches used, and the results. However, patients with the greatest preoperative stiffness had significantly better improvement of mobility (P<0.001). The best results were obtained in patients who had arthrolysis done within 1 year after the initial trauma (P=0.008). The mean SECEC scores were 88 (52 to 100) for the injured elbows, and 96 (88 to 100) for the contralateral elbows. CONCLUSION: Open elbow arthrolysis for patients with posttraumatic stiffness improves joint function and provides patient satisfaction. The best results, in terms of gain of motion and patient satisfaction, were obtained in patients with severe stiffness who had operations within the first year after initial trauma.

Germinability of Norway spruce and scots pine pollen exposed to open air

Summary

Derivation of the gauge-invariant action for open and closed free bosonic string field theories

The gauge-invariant actions for open and closed free bosonic string field theories are obtained from the string field equations in the conformal gauge using the cohomology operations of Banks and Peskin. For the closed-string theory no restrictions are imposed on the gauge parameters.

Ammonia losses estimated by an open collector from urea applied to sugarcane straw

The quantification of ammonia (NH3) losses from sugarcane straw fertilized with urea can be performed with collectors that recover the NH3 in acid-treated absorbers. Thus, the use of an open NH3 collector with a polytetrafluoroethylene (PTFE)-wrapped absorber is an interesting option since its cost is low, handling easy and microclimatic conditions irrelevant. The aim of this study was to evaluate the efficiency of an open collector for quantifying NH3-N volatilized from urea applied over the sugarcane straw. The experiment was carried out in a sugarcane field located near Piracicaba, São Paulo, Brazil. The NH3-N losses were estimated using a semi-open static collector calibrated with 15N (reference method) and an open collector with an absorber wrapped in PTFE film. Urea was applied to the soil surface in treatments corresponding to rates of 50, 100, 150 and 200 kg ha-1 N. Applying urea-N fertilizer on sugarcane straw resulted in losses NH3-N up to 24 % of the applied rate. The amount of volatile NH3-N measured in the open and the semi-open static collector did not differ. The effectiveness of the collection system varied non-linearly, with an average value of 58.4 % for the range of 100 to 200 kg ha-1 of urea-N. The open collector showed significant potential for use; however, further research is needed to verify the suitability of the proposed method.

Dynamically generated open-charm baryons beyond the zero-range approximation

The interaction of the low-lying pseudoscalar mesons with the ground-state baryons in the charm sector is studied within a coupled-channel approach using a t-channel vector-exchange driving force. The amplitudes describing the scattering of the pseudoscalar mesons off the ground-state baryons are obtained by solving the Lippmann-Schwinger equation. We analyze in detail the effects of going beyond the t=0 approximation. Our model predicts the dynamical generation of several open-charm baryon resonances in different isospin and strangeness channels, some of which can be clearly identified with recently observed states.

Evaporation and coarsening dynamics with open boundaries

We present a study of the evaporation dynamics of a substance undergoing a coarsening process. The system is modeled by the Cahn-Hilliard equation with absorbing boundaries. We have found that the dynamics, although of a diffusive nature, is much slower than the usual one without coarsening. Analytical and simulation results are in reasonable agreement.

Minimally invasive versus open transforaminal lumbar interbody fusion: evaluating initial experience.

The aim of this study was to compare our experience with minimally invasive transforaminal lumbar interbody fusion (MITLIF) and open midline transforaminal lumbar interbody fusion (TLIF). A total of 36 patients suffering from isthmic spondylolisthesis or degenerative disc disease were operated with either a MITLIF (n = 18) or an open TLIF technique (n = 18) with an average follow-up of 22 and 24 months, respectively. Clinical outcome was assessed using the visual analogue scale (VAS) and the Oswestry disability index (ODI). There was no difference in length of surgery between the two groups. The MITLIF group resulted in a significant reduction of blood loss and had a shorter length of hospital stay. No difference was observed in postoperative pain, initial analgesia consumption, VAS or ODI between the groups. Three pseudarthroses were observed in the MITLIF group although this was not statistically significant. A steeper learning effect was observed for the MITLIF group.

Comparison between the use of open and walled platforms by juvenile blue foxes (Alopex lagopus)

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