Bleeding Outcomes in Patients Treated With Asundexian in Phase II Trials.

BACKGROUND: Phase II trials of asundexian were underpowered to detect important differences in bleeding. OBJECTIVES: The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding. METHODS: We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. RESULTS: In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding. CONCLUSIONS: Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

Anticoagulant treatment for venous thromboembolism: A pooled analysis and additional results of the XALIA and XALIA-LEA noninterventional studies.

BACKGROUND: The XALIA and XALIA-LEA prospective, noninterventional studies investigated the safety and effectiveness of rivaroxaban versus standard anticoagulation for venous thromboembolism (VTE) treatment in routine clinical practice across global regions. OBJECTIVES: This pooled analysis combined their data to determine the incidence of thromboembolic and bleeding events in both treatment groups and addressed specific bleeding patterns in a broad range of patients. METHODS: Patients with objectively confirmed VTE and an indication for ≥3 months' anticoagulation treatment received rivaroxaban or standard anticoagulation (eg, initial treatment with heparin/fondaparinux, followed by a vitamin K antagonist [VKA]). Treatment choice, dose, management, and duration were at the physician's discretion. Primary outcomes (major bleeding, recurrent VTE, and all-cause mortality) were compared between the two treatment groups. Propensity score stratification, and matching were used to reduce bias due to confounding variables. RESULTS: Overall, 7129 patients were enrolled from 36 countries; 6445 and 2714 patients were included in the propensity score-stratified and -matched analyses, respectively. Major bleeding and incidences of recurrent VTE were similar between treatment groups; all-cause mortality was lower with rivaroxaban than with standard anticoagulation. The incidences of genitourinary bleeding were higher with rivaroxaban than with standard anticoagulation therapy (46 and 23 events in the matched analysis, respectively). VKA management in real-world practice was suboptimal. CONCLUSION: XALIA and XALIA-LEA show similar safety and effectiveness profiles of rivaroxaban and standard anticoagulation for VTE treatment in routine practice in many parts of the world. The observations are consistent with results from the phase III EINSTEIN randomized controlled trials.

XALIA-LEA: An observational study of venous thromboembolism treatment with rivaroxaban and standard anticoagulation in the Asia-Pacific, Eastern Europe, the Middle East, Africa and Latin America.

INTRODUCTION: The prospective, non-interventional XALIA study investigated the safety and effectiveness of rivaroxaban and standard anticoagulation for the treatment of deep vein thrombosis (DVT). XALIA-LEA was conducted in regions not included in XALIA (Latin America, Eastern Europe, the Middle East, Africa, and the Asia-Pacific), and enrolled patients with isolated pulmonary embolism (PE). MATERIALS AND METHODS: Adult patients with acute venous thromboembolism (VTE) indicated for ≥3 months' anticoagulant treatment were eligible; treatment strategies were at the physician's discretion. Patients receiving rivaroxaban or standard anticoagulation (unfractionated or low-molecular weight heparin/fondaparinux alone or overlapping with and followed by a vitamin K antagonist [VKA]) were included in the safety analysis. "Early switchers" to rivaroxaban (i.e. after receiving heparin/fondaparinux for >2-14 days and/or a VKA for 1-14 days) were not included in the safety analysis set. RESULTS: Of the 1972 eligible patients, 1285 received rivaroxaban, 402 received standard anticoagulation, and 285 were early switchers. Most patients who received rivaroxaban were appropriately selected, received the correct dosing schedule, reported few adverse effects. Outcomes were similar to previously published results, with rivaroxaban associated with a low rate of major bleeding (1.6%), recurrent VTE (1.4%) and all-cause mortality (2.3%). Including early switchers, relatively fewer patients with index isolated PE received rivaroxaban (14.4%) versus standard anticoagulation therapy (20.9%). Some regional variations and differences in outcomes by VTE subtype were apparent with standard anticoagulation treatment. CONCLUSION: XALIA-LEA reaffirms the safety and effectiveness of rivaroxaban for VTE treatment for countries not included in XALIA.

Risk of recurrent venous thromboembolism according to baseline risk factor profiles.

The optimal duration of anticoagulation for venous thromboembolism (VTE) is uncertain. In this prespecified analysis, we used data from 2 randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with aspirin (100 mg) or placebo for extended VTE treatment to estimate the risk of recurrence according to baseline risk factor profiles. Index VTE events were centrally classified as unprovoked, or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at 1 year were calculated. A total of 2832 patients received rivaroxaban; 1131 received aspirin, and 590 received placebo. With unprovoked VTE, rates of recurrence in the 1173 patients given rivaroxaban, the 468 given aspirin, and the 243 given placebo were 2.0%, 5.9%, and 10.0%, respectively. There were no recurrences in patients with VTE provoked by major transient risk factors. With VTE provoked by minor persistent risk factors, recurrence rates in the 1184 patients given rivaroxaban, the 466 given aspirin, and the 248 given placebo were 2.4%, 4.5%, and 10.7%, respectively. For patients with minor transient risk factors, recurrence rates were 0.4% in the 268 patients given rivaroxaban, 4.2% in the 121 given aspirin, and 7.1% in the 56 given placebo. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.56-1.16; and HR, 0.68; 95% CI, 0.32-1.30, respectively). Therefore, such patients may also benefit from extended anticoagulation therapy.

Low acyl-CoA synthetase 5 expression in colorectal carcinomas is prognostic for early tumour recurrence.

It has been shown that the metabolism of long chain fatty acids is involved in colorectal carcinogenesis. Acyl-CoA synthetases (ACSL) activate free fatty acids by synthesis of acyl-CoA thioesters. ACSL isoform 5 (ACSL5) is involved in enterocytic differentiation and maturation by regulating both pro-apoptotic and anti-proliferative effects. Whilst impaired expression of ACSL5 has been associated with sporadic colorectal carcinogenesis, little is known about ACSL5 as a prognostic factor. Aim of this retrospective study was to characterize the prognostic impact of ACSL5 expression levels in sporadic colorectal adenocarcinomas. A total of 72 patients with a median follow-up of 54 months was included. Using a standardized immunohistochemical approach, colorectal adenocarcinomas with low (n=41; group 1) or high (n=31; group 2) ACSL5 levels were identified. In a one-year follow-up, tumour recurrence was significantly increased in group 1 (p=0.0279). The finding was independent of the TNM- and UICC-stage in the surgical resections. Frequency of lymph node metastasis and mortality was not different between the groups. In a long-time follow-up no differences were found between the ACSL5 groups. The data indicate that ACSL5 could be an independent prognostic factor for early recurrence of sporadic colorectal adenocarcinoma.

Improved technical performance of a multifunctional prehospital telemedicine system between the research phase and the routine use phase - an observational study.

Introduction Telemedical concepts in emergency medical services (EMS) lead to improved process times and patient outcomes, but their technical performance has thus far been insufficient; nevertheless, the concept was transferred into EMS routine care in Aachen, Germany. This study evaluated the system's technical performance and compared it to a precursor system. Methods The telemedicine system was implemented on seven ambulances and a teleconsultation centre staffed with experienced EMS physicians was established in April 2014. Telemedical applications included mobile vital data, 12-lead, picture transmission and video streaming from inside the ambulances. The tele-EMS physician filled in a questionnaire regarding the technical performance of the applications, background noise and assessed clinical values of the transmitted pictures and videos after each mission between 15 May 2014-15 October 2014. Results Teleconsultation was established during 539 emergency cases. In 83% of the cases ( n = 447), only the paramedics and the tele-EMS physician were involved. Transmission success rates ranged from 98% (audio connection) to 93% (12-lead electrocardiogram (ECG) transmission). All functionalities, except video transmission, were significantly better than the pilot project ( p < 0.05). Severe background noise was detected to a lesser extent ( p = 0.0004) and the clinical value of the pictures and videos were considered significantly more valuable. Discussion The multifunctional system is now sufficient for routine use and is the most reliable mobile emergency telemedicine system compared to other published projects. Dropouts were due to user errors and network coverage problems. These findings enable widespread use of this system in the future, reducing the critical time intervals until medical therapy is started.

Treatment of Acute Coronary Syndrome by Telemedically Supported Paramedics Compared With Physician-Based Treatment: A Prospective, Interventional, Multicenter Trial.

BACKGROUND: Prehospital treatment of acute coronary syndrome (ACS) in German emergency medical services (EMSs) is reserved for EMS physicians due to legal issues. OBJECTIVE: The objective of this prospective, interventional, multicenter trial was to evaluate the quality of telemedically-delegated therapy and the possible complications in patients with ACS. METHODS: After approval by the ethics committee and trial registration, a one-year study phase was started in August 2012 with 5 ambulances, telemedically equipped and staffed with paramedics, in 4 German EMS districts. The paramedics could contact an EMS-physician-staffed telemedicine center. After initiation of an audio connection, real-time data transmission was automatically established. If required, 12-lead electrocardiogram (ECG) and still pictures could be sent. Video was streamed from inside each ambulance. All drugs, including opioids, were delegated to the paramedics based on standardized, predefined algorithms. To compare telemedically-delegated medication and treatment in ACS cases with regular EMS missions, a matched pair analysis with historical controls was performed. RESULTS: Teleconsultation was performed on 150 patients having a cardiovascular emergency. In 39 cases, teleconsultation was started due to suspected ACS. No case had a medical complication. Correct handling of 12-lead ECG was performed equally between the groups (study group, n=38 vs control group, n=39, P>.99). There were no differences in correct handling of intravenous administration of acetylsalicylic acid, heparin, or morphine between both the groups (study group vs control group): acetylsalicylic acid, n=31 vs n=33, P=.73; unfractionated heparin, n=34 vs n=33, P>.99; morphine, n=29 vs n=27, P=.50. The correct handling of oxygen administration was significantly higher in the study group (n=29 vs n=18, P=.007). CONCLUSIONS: Telemedical delegation of guideline conform medication and therapy by paramedics in patients with ACS and was found to be feasible and safe. The quality of guideline-adherent therapy was not significantly different in both the groups except for the correct administration of oxygen, which was significantly higher in the study group. TRIAL REGISTRATION: Clinicaltrials.gov NCT01644006; http://clinicaltrials.gov/ct2/show/NCT01644006 (Archived by WebCite at http://www.webcitation.org/6mPam3eDy).

Prevalence of periodontitis in individuals with human leukocyte antigens (HLA) A9, B15, A2, and B5.

OBJECTIVE: Human leukocyte antigens (HLA) have been associated with periodontitis. Previous studies revealed HLA-A9 and HLA-B15 as potential susceptibility factors, while HLA-A2 and HLA-B5 might have protective effects. The aim of the study was to verify these associations in a group of HLA-typed blood donors with previously unknown periodontal status. MATERIALS AND METHODS: In four German centers, 140 blood donors with known HLA class I status were enrolled and allocated to the following five groups: HLA-A9 (N = 24), HLA-B15 (N = 20), HLA-A2 (N = 30), HLA-B5 (N = 26), and controls (N = 40). Periodontal examination included the measurement of probing depths (PDs), clinical attachment level (CAL), bleeding on probing (BOP), and community periodontal index of treatment needs (CPITN). RESULTS: Carriers with HLA-A9 and HLA-B15 had higher values of mean PD (P < 0.0001), CAL (P < 0.0001), and BOP (P < 0.002) as well as sites with PD and CAL with ≥4 and ≥6 mm (P < 0.0003), respectively, than controls. Multiple regression analyses revealed HLA-A9, HLA-B15, and smoking as risk indicators for moderate to severe (CPITN 3-4; odds ratio (OR): 66.7, 15.3, and 5.1) and severe (CPITN 4; OR: 6.6, 7.4, and 3.8) periodontitis. HLA-A2 and HLA-B5 did not show any relevant associations. CONCLUSION: The present data support a role of HLA-A9 and HLA-B15 as susceptibility factors for periodontitis, whereas HLA-A2 and HLA-B5 could not be confirmed as resistance factors. CLINICAL RELEVANCE: Both HLA antigens A9 and B15 are potential candidates for periodontal risk assessment.

Vitamin K antagonism aggravates chronic kidney disease-induced neointimal hyperplasia and calcification in arterialized veins: role of vitamin K treatment?

Arteriovenous fistula (AVF) is the common vascular access type for a hemodialysis patient. Its failure is due to neointimal hyperplasia. Vitamin K antagonists are given to lower thrombosis tendency, but have side effects that enhance arterial calcifications. Here, we investigated the effects of vitamin K antagonists and vitamin K2 (K2) treatment on neointimal hyperplasia development and calcification in rats and in arterialized human veins. AVF was generated in female rats while chronic kidney disease (CKD) was induced using an adenine-enriched diet. Arterialization, CKD, and vitamin K antagonists all significantly enhanced venous neointimal hyperplasia. K2 treatment, additional to vitamin K antagonists, significantly reduced neointimal hyperplasia in arterialized veins in healthy rats but not in rats with CKD. Arterialization, CKD, and vitamin K antagonism all significantly increased, whereas K2 supplementation attenuated calcification in healthy rats and rats with CKD. K2 significantly enhanced matrix Gla protein carboxylation in control rats and rats with CKD. Arterialized human vein samples contained inactive matrix Gla protein at calcification and neointimal hyperplasia sites, indicating local vitamin K deficiency. Thus, vitamin K antagonists have detrimental effects on AVF remodeling, whereas K2 reduced neointimal hyperplasia and calcification indicating vasoprotective effects. Hence, K2 administration may be useful to prevent neointimal hyperplasia and calcification in arterialized veins

Selective renal blood perfusion induces renal tubules injury in a porcine model.

OBJECTIVE: Extracorporeal circulation is routinely used in thoracoabdominal aortic aneurysm repair to preserve blood perfusion. Despite this protective measure, acute and chronic kidney disorders can develop. Therefore, the aim of this study was to establish a new large-animal model to assess the efficacy of selective renal perfusion (SRP) with extracorporeal circulation in a setting of thoracoabdominal aortic aneurysm repair. METHODS: Eighteen pigs underwent a thoracolaparotomy, during with the aorta and renal arteries were exposed. The animals were divided into three cohorts of six pigs each: cohort I--control; cohort II--thoracic aortic clamping with distal aortic perfusion (DAP) using a roller pump; and cohort III--thoracic aortic clamping with DAP plus SRP. Kidney metabolism, kidney injury, and red blood cell damage were measured by oxygen extraction ratio (O2ER), neutrophil gelatinase-associated lipocalin, a marker for acute kidney damage, and serum free hemoglobin. RESULTS: With normal mean arterial blood pressures, flow rates in the renal arteries during perfusion decreased to 75% (group II) with DAP and to 50% (group III) with SRP compared with the control animals (group I; P = .0279 for I vs II; P = .0002 for I vs III). Microcirculation, measured by microspheres, did not differ significantly among the groups. In contrast, O2ER (P = .0021 for I vs III) and neutrophil gelatinase-associated lipocalin (P = .0083 for I vs III) levels were significantly increased in group III, whereas free hemoglobin was increased in groups II and III (P = .0406 for I vs II; P = .0018 for I vs III). CONCLUSIONS: SRP with a roller pump induces kidney tubule injury. Thus, distal aortic and SRP in our model does not provide adequate kidney protection. Furthermore, the perfusion system provokes red blood cell damage with increased free hemoglobin. Hence, the SRP perfusion technique should be revised and tested.

Extracorporeal circulation increases proliferation in the intestinal mucosa in a large animal model.

OBJECTIVE: Extracorporeal circulation induces ischemia/reperfusion injury in the small intestinal wall. One reason for this damage is a perfusion shift from the muscular toward the mucosal layer. This study investigated the effect of this perfusion shift on the small-intestinal apoptosis and proliferation. METHODS: Twenty-eight pigs were randomly assigned to the following cohorts and underwent a thoracolaparotomy and a 1 hour main procedure: cohort I: control; cohort II: thoracic aortic cross-clamping (TAC) without perfusion; cohort III: TAC and distal aortic perfusion (DAP); cohort IV: TAC, DAP, and selective visceral perfusion. The main procedure was followed by 2 hours of reperfusion in all cohorts. Tissue samples were taken during the experiment, stained, and analyzed for apoptosis and proliferation (caspase-3, annexin-V, terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling, and proliferating cell nuclear antigen). Six animals died unexpectedly during the experiment and were excluded from the analysis. RESULTS: Extensive tissue damage and necrosis was only found in cohort II after the main procedure. In the mucosa, the proliferation was increased in cohort III at the end of the experiment (P = .0157 cohort I vs II). In contrast, the annexin-V/proliferating cell nuclear antigen ratio was significantly higher in cohorts II and IV than in cohorts I and II at the end of the experiment (P = .0034). Furthermore, the caspase-3/annexin-V ratio was increased in all cohorts at the end of the experiment (P = .0015). CONCLUSIONS: Mucosal proliferation is the early repair mechanism of the limited small intestinal ischemia/reperfusion injury after DAP. Furthermore, the extensive surgical trauma shifted the mucosal apoptosis into an advanced state.

Radiological surveillance of formerly asbestos-exposed power industry workers: rates and risk factors of benign changes on chest X-ray and MDCT.

BACKGROUND: To determine the prevalence of asbestos-related changes on chest X-ray (CXR) and low-dose multidetector-row CT (MDCT) of the thorax in a cohort of formerly asbestos-exposed power industry workers and to assess the importance of common risk factors associated with specific radiological changes. METHODS: To assess the influence of selected risk factors (age, time since first exposure, exposure duration, cumulative exposure and pack years) on typical asbestos-related radiographic changes, we employed multiple logistic regression and receiver operating characteristic (ROC) analysis. RESULTS: On CXR, pleural changes and asbestosis were strongly associated with age, years since first exposure and exposure duration. The MDCT results showed an association between asbestosis and age and between plaques and exposure duration, years since first exposure and cumulative exposure. Parenchymal changes on CXR and MDCT, and diffuse pleural thickening on CXR were both associated with smoking. Using a cut-off of 55 years for age, 17 years for exposure duration and 28 years for latency, benign radiological changes in the cohort with CXR could be predicted with a sensitivity of 82.0% for all of the three variables and a specificity of 47.4%, 39.0% and 40.6%, respectively. CONCLUSIONS: Participants aged 55 years and older and those with an asbestos exposure of at least 17 years or 28 years since first exposure should be seen as having an increased risk of abnormal radiological findings. For implementing a more focused approach the routine use of low-dose MDCT rather than CXR at least for initial examinations would be justified.

The gingival biotype: measurement of soft and hard tissue dimensions - a radiographic morphometric study.

BACKGROUND: Gingival biotypes have been reported to influence the outcome of restorative therapies. The aim of this study was to evaluate the correlation of different morphometric parameters with the thickness of the buccal gingiva and alveolar bone at different apico-coronal levels. METHODS: In 60 periodontally healthy subjects, the central maxillary incisor was examined. Clinical parameters included the crown width/crown length ratio (CW/CL), gingival width (GW), gingival scallop (SC) and transparency of the periodontal probe through the gingival sulcus (TRAN). Gingival and alveolar bone dimensions were assessed on parallel profile radiographs. RESULTS: Crown width/crown length ratio was positively correlated with the thickness of the gingiva at the cementoenamel junction (G3) (r = 0.47) and to the thickness of the alveolar crest (A1) (r = 0.46); whereas SC had a weak negative and GW had a moderate positive correlation with all radiographic measurements. TRAN had a stronger negative relation to the thickness at the free gingiva (r = -0.42) than to other tissue thicknesses. All gingival thickness values were correlated with A1 value. Multivariate models identified CW/CL and GW as significant predictors for G3 value, whereas CW/CL was a significant predictor for A1 value. CONCLUSION: Crown width/crown length ratio and GW could represent surrogate parameters to anticipate the gingival thickness at the cementoenamel junction, whereas CW/CL might also be an indicator for alveolar bone crest thickness. Periodontal probing has a limited prognostic value for these tissue dimensions.

Full field image reconstruction is suitable for high-pitch dual-source computed tomography.

OBJECTIVES: The field of view (FOV) in high-pitch dual-source computed tomography (DSCT) is limited by the size of the second detector. The goal of this study was to develop and evaluate a full FOV image reconstruction technique for high-pitch DSCT. MATERIALS AND METHODS: For reconstruction beyond the FOV of the second detector, raw data of the second system were extended to the full dimensions of the first system, using the partly existing data of the first system in combination with a very smooth transition weight function. During the weighted filtered backprojection, the data of the second system were applied with an additional weighting factor. This method was tested for different pitch values from 1.5 to 3.5 on a simulated phantom and on 25 high-pitch DSCT data sets acquired at pitch values of 1.6, 2.0, 2.5, 2.8, and 3.0. Images were reconstructed with FOV sizes of 260 × 260 and 500 × 500 mm. Image quality was assessed by 2 radiologists using a 5-point Likert scale and analyzed with repeated-measure analysis of variance. RESULTS: In phantom and patient data, full FOV image quality depended on pitch. Where complete projection data from both tube-detector systems were available, image quality was unaffected by pitch changes. Full FOV image quality was not compromised at pitch values of 1.6 and remained fully diagnostic up to a pitch of 2.0. At higher pitch values, there was an increasing difference in image quality between limited and full FOV images (P = 0.0097). CONCLUSION: With this new image reconstruction technique, full FOV image reconstruction can be used up to a pitch of 2.0.

Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG.

BACKGROUND: The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Children's Oncology Group [NPC-2003-GPOH/DCOG]). METHODS: From 2003 to 2010, 45 patients (ages 8-20 years), including 1 patient with stage II NPC and 44 patients with stage III/IV NPC, were recruited to the study. The patient with stage II disease received radiotherapy (59.4 grays [Gy]). The patients with stage III/IV disease received 3 courses of neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and folinic acid. The cumulative irradiation dose was 54 Gy in 5 patients, who achieved complete remission after neoadjuvant chemotherapy, and 59.4 Gy in the remaining 40 patients. All patients received concomitant cisplatin during the first week and last week of irradiation. After irradiation, all patients received interferon beta for 6 months. Tumor response was evaluated by magnetic resonance imaging studies and positron emission tomography scans. RESULTS: After the completion of treatment, 43 of 45 patients were in complete remission. In 2 patients, only a partial response was achieved, followed by distant metastases (1 patient) or local progression and distant metastases (1 patient), 6 months and 10 months after diagnosis, respectively. Another patient developed a solitary pelvic bone metastasis 21 months after diagnosis. After a median follow-up of 30 months (range, 6-95 months), the event-free survival rate was 92.4%, and the overall survival was 97.1%. Acute toxicity consisted mainly of leucopenia, mucositis, and nausea; and late toxicity consisted of hearing loss and hypothyroidism. CONCLUSIONS: Combined therapy with neoadjuvant chemotherapy, radiochemotherapy, and interferon beta was well tolerated and resulted in a very good outcome that was superior to the outcomes of published results from all other pediatric NPC study groups.