Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK)

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

Transient Benign Hyperphophatasemia - A Systematic Review of The Literature

BACKGROUND:: Sometimes, a temporary increase in alkaline phosphatase level is found in healthy infants and toddlers without evidence of liver or bone disease. The condition is customarily termed transient benign hyperphosphatasemia of infancy and early childhood. Most textbooks do not refer to the condition. METHODS:: We completed a systematic review of the literature using the principles underlying the UK Economic and Social Research Council guidance on the conduct of narrative synthesis and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS:: The 142 reports retained for analysis included 813 cases (male:female ratio = 1.1:1.0): 80 in subjects >18 years and 733 in subjects ≤18 years of age. The alkaline phosphatase ratio, calculated by dividing the measured level by the upper normal limit, was ≥5.0 in ≈70% and the duration of the elevation ≤4 months in 80% of the cases. Transient benign hyperphosphatasemia often followed a benign infection but available data fail to demonstrate a causal link. The prevalence of transient benign hyperphosphatasemia ranged 1.1-3.5% in infants 2 to 24 months of age. CONCLUSIONS:: Transient benign hyperphosphatasemia is likely the most common cause of hyperphosphatasemia among healthy infants and toddlers. Sometimes, it also occurs in older children and adults, indicating that the traditional term transient benign hyperphosphatasemia of infancy and early childhood might not be correct. The elevation in alkaline phosphatase persists for >4 months in ≈20% of the cases. Recognition of this benign condition is crucial to avoid unnecessary investigations.

Intra-articular calcium phosphate cement: Its fate and impact on joint tissues in a rabbit model

Clinical application of injectable ceramic cement in comminuted fractures revealed penetration of the viscous paste into the joint space. Not much is known on the fate of this cement and its influence on articular tissues. The purpose of this experimental study was to assess these unknown alterations of joint tissues after intra-articular injection of cement in a rabbit knee. Observation periods were from 1 week up to 24 months, with three rabbits per group. Norian SRS cement was injected into one knee joint, the contralateral side receiving the same volume of Ringers' solution. Light microscopic evaluation of histologic sections was performed, investigating the appearance of the cement, inflammatory reactions, and degenerative changes of the articular surface. No signs of pronounced acute or chronic inflammation were visible. The injected cement was mainly found as a single particle, anterior to the cruciate ligaments. It became surrounded by synovial tissues within 4 weeks and showed signs of superficial resorption. In some specimens, bone formation was seen around the cement. Degeneration of the articular surface showed no differences between experimental and control side, and no changes over time became apparent. No major degenerative changes were induced by the injected cement. The prolonged presence of cement still seems to make it advisable to remove radiologically visible amounts from the joint space.

Elective neck dissection for carcinomas of the oral cavity: occult metastases, neck recurrences, and adjuvant treatment of pathologically positive necks

BACKGROUND: Supraomohyoid neck dissection (SOHND) is currently performed in patients with carcinoma of the oral cavity with clinically negative neck. Most investigators consider SOHND as a staging procedure. METHODS: Records of 100 patients with cancer of the oral cavity and clinically negative neck undergoing SOHND were reviewed. The rate and significance of occult metastases are evaluated, the neck recurrences are analyzed and the indication of adjuvant radiation of pN+ necks is discussed. RESULTS: In 34 of 1814 of analyzed lymph nodes, metastatic disease was detected as follows: 30 macrometastases and 4 micrometastases. In 13 of 34 metastases (38%), extracapsular spread was observed. Twenty of 100 patients (20%) had to be upstaged. In 9 of 87 (10%) patients without local recurrence and with a minimal follow-up of 24 months, 5 ipsilateral (4 within the dissection field) and 5 contralateral neck recurrences were observed. Regional recurrence developed in 4% and 35% of patients with pN0 and pN+ necks, respectively. CONCLUSIONS: In 20% of patients with oral cavity tumors and pN0 neck, occult metastases were disclosed. Neck recurrences developed significantly more often in patients with pN+ than in those with pN0 necks. To evaluate the exact indication for an adjuvant treatment of patients with cN0/pN+ necks, prospective studies should be performed.

Neuropsychological problems after paediatric stroke: two year follow-up of Swiss children

AIM: The aim of this study was to obtain information about neurological and cognitive outcome for a population-based group of children after paediatric ischaemic stroke. METHODS: Data from the Swiss neuropaediatric stroke registry (SNPSR), from 1.1.2000 to 1.7.2002, including children (AIS 1) and neonates (AIS 2). At 18-24 months after a stroke, a follow-up examination was performed including a history, neurological and neuropsychological assessment. RESULTS: 33/48 children (22 AIS 1, 11 AIS 2) participated in the study. Neurological outcome was good in 16/33. After childhood stroke mean IQ levels were normal (94), but 6 children had IQ < 85 (50-82) and neuropsychological problems were present in 75%. Performance IQ (93) was reduced compared to verbal IQ (101, p = 0.121) due to problems in the domain of processing speed (89.5); auditory short-term memory was especially affected. Effects on school career were common. Outcome was worse in children after right-sided infarction. Children suffering from stroke in mid-childhood had the best prognosis. There was no clear relationship between outcome and localisation of the lesion. After neonatal stroke 7/11 children showed normal development and epilepsy indicated a worse prognosis in the remaining 4. CONCLUSION: After paediatric stroke neuropsychological problems are present in about 75% of children. Younger age at stroke as well as an emergence of epilepsy were predictors for worse prognosis.

Population-based epidemiology of rotavirus hospitalisations in Switzerland

BACKGROUND: Rotaviruses (RV) are the most common cause of dehydrating gastroenteritis requiring hospitalisation in children <5 years of age. A new generation of safe and effective RV vaccines is available. Accurate data describing the current burden of RV disease in the community are needed to devise appropriate strategies for vaccine usage. METHODS: Retrospective, population-based analysis of RV hospitalisations in children <5 years of age during a 5-year period (1999-2003) in a both urban and rural area inhabited by 12% of the Swiss population. RESULTS: Of 406 evaluable cases, 328 were community-acquired RV infections in children <5 years of age. RV accounted for 38% of all hospitalisations for gastroenteritis. The overall hospitalisation incidence in the <5-year-old was 1.5/1000 child-years (peak incidence, 2.6/1000 child-years in children aged 13-24 months). The incidence of community-acquired RV hospitalisations was significantly greater in children of non-Swiss origin (3.0 vs. 1.1/1000 child-years, relative risk 2.7; 95% CI 2.2-3.4), who were younger, but tended to be less severely dehydrated on admission than Swiss children. In comparison with children from urban areas, RV hospitalisation incidence was significantly lower among those residing in the remote mountain area (0.71 vs. 1.71/1000 child years, relative risk 2.2, 95% CI 1.6-3.1). CONCLUSION: Population-based RV hospitalisation incidence was low in comparison with other European countries. Significantly greater hospitalisation rates among children living in urban areas and those from non-Swiss families indicate that factors other than the severity of RV-induced dehydration are important driving forces of hospital admission.

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.

Short anterior correction of the thoracolumbar/lumbar curve in King 1 idiopathic scoliosis: the behaviour of the instrumented and non-instrumented curves and the trunk balance

This is a retrospective clinical, radiological and patient outcome assessment of 21 consecutive patients with King 1 idiopathic adolescent scoliosis treated by short anterior selective fusion of the major thoracolumbar/lumbar (TL/L) curve. Three-dimensional changes of both curves, changes in trunk balance and rib hump were evaluated. The minimal follow-up was 24 months (max. 83). The Cobb angle of the TL/L curve was 52 degrees (45-67 degrees) with a flexibility of 72% (40-100%). The average length of the main curve was 5 (3-8) segments. An average of 3 (2-4) segments was fused using rigid single rod implants with side-loading screws. The Cobb angle of the thoracic curve was 33 degrees (18-50 degrees) with a flexibility of 69% (29-100%). The thoracic curve in bending was less than 20 degrees in 17 patients, and 20-25 degrees in 4 patients. In the TL/L curve there was an improvement of the Cobb angle of 67%, of the apex vertebral rotation of 51% and of the apex vertebral translation of 74%. The Cobb angle of the thoracic curve improved 29% spontaneously. Shoulder balance improved significantly from an average preoperative imbalance of 14.5-3.1 mm at the last follow-up. Seventy-five percent of the patients with preoperative positive shoulder imbalance (higher on the side of the thoracic curve) had levelled shoulders at the last follow-up. C7 offset improved from a preoperative 19.8 (0-40) to 4.8 (0-18) mm at the last follow-up. There were no significant changes in rotation, translation of the thoracic curve and the clinical rib hump. There were no significant changes in thoracic kyphosis or lumbar lordosis. The average score of the SRS-24 questionnaire at the last follow-up was 91 points (max. 120). We conclude that short anterior selective fusion of the TL/L curve in King 1 scoliosis with a thoracic curve bending to 25 degrees or less (Type 5 according to Lenke classification) results in a satisfactory correction and a balanced spine. Short fusions leave enough mobile lumbar segments for the establishment of global spinal balance. A positive shoulder imbalance is not a contraindication for this procedure. Structural interbody grafts are not necessary to maintain lumbar lordosis.

Internet based multicenter study for thoracolumbar injuries: a new concept and preliminary results

This article reports about the internet based, second multicenter study (MCS II) of the spine study group (AG WS) of the German trauma association (DGU). It represents a continuation of the first study conducted between the years 1994 and 1996 (MCS I). For the purpose of one common, centralised data capture methodology, a newly developed internet-based data collection system ( http://www.memdoc.org ) of the Institute for Evaluative Research in Orthopaedic Surgery of the University of Bern was used. The aim of this first publication on the MCS II was to describe in detail the new method of data collection and the structure of the developed data base system, via internet. The goal of the study was the assessment of the current state of treatment for fresh traumatic injuries of the thoracolumbar spine in the German speaking part of Europe. For that reason, we intended to collect large number of cases and representative, valid information about the radiographic, clinical and subjective treatment outcomes. Thanks to the new study design of MCS II, not only the common surgical treatment concepts, but also the new and constantly broadening spectrum of spine surgery, i.e. vertebro-/kyphoplasty, computer assisted surgery and navigation, minimal-invasive, and endoscopic techniques, documented and evaluated. We present a first statistical overview and preliminary analysis of 18 centers from Germany and Austria that participated in MCS II. A real time data capture at source was made possible by the constant availability of the data collection system via internet access. Following the principle of an application service provider, software, questionnaires and validation routines are located on a central server, which is accessed from the periphery (hospitals) by means of standard Internet browsers. By that, costly and time consuming software installation and maintenance of local data repositories are avoided and, more importantly, cumbersome migration of data into one integrated database becomes obsolete. Finally, this set-up also replaces traditional systems wherein paper questionnaires were mailed to the central study office and entered by hand whereby incomplete or incorrect forms always represent a resource consuming problem and source of error. With the new study concept and the expanded inclusion criteria of MCS II 1, 251 case histories with admission and surgical data were collected. This remarkable number of interventions documented during 24 months represents an increase of 183% compared to the previously conducted MCS I. The concept and technical feasibility of the MEMdoc data collection system was proven, as the participants of the MCS II succeeded in collecting data ever published on the largest series of patients with spinal injuries treated within a 2 year period.

Quality and quantity of bone following alveolar distraction osteogenesis in the human mandible

PURPOSE: The purpose of this prospective study on humans were to evaluate (a) the clinical outcome of alveolar distraction osteogenesis for the correction of vertically deficient edentulous mandibular ridges, (b) the clinical outcome of dental implants placed in the distracted areas, and (c) the quality and quantity of the bone that had formed in the distraction gap. MATERIAL AND METHODS: Seven patients presenting vertically deficient edentulous ridges were treated by means of distraction osteogenesis with an intraoral alveolar distractor. Approximately 3 months after consolidation of the distracted segments, 20 ITI solid screw SLA implants were placed in the distracted areas. Three to 4 months later, abutments were connected and prosthetic loading of the implants started. During implant site preparation, bone biopsies were taken at the implant sites with trephine burrs for histologic and histometric analyses. RESULTS: The mean follow-up after the initial prosthetic loading was 18 months (range 12-24 months). The mean bone gain obtained at the end of distraction was 7 mm (range 5-9 mm). The cumulative success rate of implants 2 years after the onset of prosthetic loading was 95%, whereas the survival rate of implants was 100%. The newly formed bone consisted of woven bone reinforced by parallel-fibered bone with bone marrow spaces between the bone trabeculae. The bone area fraction in the distraction region ranged from 21.6% to 57.8% (38.5+/-11.7%). DISCUSSION AND CONCLUSIONS: Results from this study showed that (a) distraction osteogenesis is a reliable technique for the correction of vertically deficient edentulous ridges, (b) the regenerated bone withstood the functional demands of implant loading, (c) survival and success rates of implants placed in the distracted areas were consistent with those of implants placed in native bone, and (d) there is sufficient bone volume and maturity in the distracted region for primary stability of the implant.

A parent-completed respiratory questionnaire for 1-year-old children: repeatability

BACKGROUND AND AIMS: There are few standardised questionnaires for the assessment of respiratory symptoms in preschool children. We have developed and tested the short-term repeatability of a postal questionnaire on respiratory symptoms for 1-year-old children. METHODS: A newly developed postal questionnaire for the assessment of wheeze and other respiratory symptoms was sent to parents of a population-based random sample of 4300 children aged 12-24 months. After an interval of 3 months, a random sample of 800 respondents received the questionnaire a second time. The responses were compared using Cohen's kappa (kappa) to assess agreement corrected for chance. RESULTS: The first questionnaire was returned by 3194 (74%) families, the second one by 460/800 (58%). Repeatability was excellent (kappa 0.80-0.96) for questions on household characteristics, environmental exposures and family history, good (kappa 0.61-0.80) for questions on prevalence, severity and treatment of wheeze, and moderate (kappa 0.39-0.66) for chronic cough and upper respiratory symptoms. CONCLUSIONS: This short postal questionnaire designed for use in population-based studies has excellent repeatability for family and household characteristics and good repeatability for questions on wheeze. Short-term changes in symptom status might be responsible for variable answers on recent chronic cough and upper respiratory symptoms. Overall, the questionnaire is a valuable instrument for community-based research on respiratory symptoms in 1 to 2-year-old children.

Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment

Ectopic acromegaly represents less than 1% of the reported cases of acromegaly. Although clinical improvement is common after treatment with somatostatin (SMS) analogs, the biochemical response and tumor size of the growth hormone-releasing hormone (GHRH)-producing tumor and its metastases are less predictable. Subject A 36-year-old male was referred because of a 3-year history of acromegaly related symptoms. He had undergone lung surgery in 1987 for a "benign" carcinoid tumor. Endocrine evaluation confirmed acromegaly Plasma IGF-1: 984 ng/ml (63-380), GH: 49.8 ng/ml (<5). MRI showed a large mass in the left cerebellopontine angle and diffuse pituitary hyperplasia. Pulmonary, liver and bone metastases were shown by chest and abdominal CT scans. Ectopic GHRH secretion was suspected. Methods Measurement of circulating GHRH levels by fluorescence immunoassay levels and immunohistochemical study of the primary lung tumor and metastatic tissue with anti-GHRH and anti-somatostatin receptor type 2 (sst2A) antibodies. Results Basal plasma GHRH: 4654 pg/ml (<100). Pathological study of liver and bone biopsy material and lung tissue removed 19 years earlier was consistent with an atypical carcinoid producing GHRH and exhibiting sst2A receptor expression. Treatment with octreotide LAR 20-40 mg q. month resulted in normalization of plasma IGF-1 levels. Circulating GHRH levels decreased dramatically. The size of the left prepontine cistern mass, with SMS receptors shown by a radiolabeled pentetreotide scan, decreased by 80% after 18 months of therapy. Total regression of pituitary enlargement was also observed. No changes were observed in lung and liver metastases. After 24 months of therapy the patient is asymptomatic and living a full and active life.

Respiratory syncytial virus infection in 406 hospitalized premature infants: results from a prospective German multicentre database

Premature birth, chronic lung disease of prematurity (CLD), congenital heart disease and immunodeficiency predispose to a higher morbidity and mortality in respiratory syncytial virus (RSV) infection. This study describes the preterms hospitalised with RSV infection from the prospective German DSM RSV Paed database. The DMS RSV Paed database was designed for the prospective multicentre documentation and analysis of clinically relevant aspects of the management of inpatients with RSV infection. This study covers six consecutive RSV seasons (1999-2005); the surveillance took place in 14 paediatric hospitals in Germany. Of the 1,568 prospectively documented RSV infections, 26% (n=406) were observed in preterms [vs. 1,162 children born at term (74%)] and 3% (n=50) had CLD, of which 49 had received treatment in the last 6 months ('CLDplus'). A significantly higher proportion in the preterm group had congenital heart disease, nosocomial infection, and neuromuscular impairment. There were significantly more children older than 24 months in the preterm group. The attributable mortality was 0.2% (n=2) in children born at term vs. 1.2% (n=5) in the preterm group (p=0.015) [preterm plus CLD 8.0% (n=4 of 50); McIntosh grade 1, 8.6% (n=3 of 35) and McIntosh Grade 4, 15% (n=3 of 20)]. Eight patients were categorized as 'palivizumab failures'. In the multivariate analysis, premature birth, CLD(plus), and nosocomial infection were significantly and independently associated with the combined outcome 'complicated course of disease'. In conclusion, this is the first prospective multicentre study from Germany that confirms the increased risk for severe RSV disease in preterms, in particular in those with CLD treated in the last 6 months before the onset of the infection. From the perspective of our results, the statements of the German Society of Paediatric Infectious Diseases considering the use of passive immunisation (2003) seem reasonable.

Influence of pulmonary status and diabetes mellitus on aortic neck dilatation following endovascular repair of abdominal aortic aneurysms: a EUROSTAR report

PURPOSE: To elucidate the association of impaired pulmonary status (IPS) and diabetes mellitus (DM) with clinical outcome and the incidences of aortic neck dilatation and type I endoleak after elective endovascular infrarenal aortic aneurysm repair (EVAR). METHODS: In 164 European institutions participating in the EUROSTAR registry, 6383 patients (5985 men; mean age 72.4+/-7.6 years) underwent EVAR. Patients were divided into patients without versus with IPS or with/without DM. Clinical assessment and contrast-enhanced computed tomography (CT) were performed at 1, 3, 6, 12, 18, and 24 months and annually thereafter. Cumulative endpoint analysis comprised death, aortic rupture, type I endoleak, endovascular reintervention, and surgical conversion. RESULTS: Prevalence of IPS was 2733/6383 (43%) and prevalence of DM was 810/6383 (13%). Mean follow-up was 21.1+/-18.4 months. Thirty-day mortality, AAA rupture, and conversion rates did not differ between patients with versus without IPS and between patients with versus without DM. All-cause and AAA-related mortality, respectively, were significantly higher in patients with IPS compared to patients with normal pulmonary status (31.0% versus 19.0%, p<0.0001 and 6.8% versus 3.3%, p = 0.0057) throughout follow-up. In multivariate analysis adjusted for smoking, age, gender, comorbidities, fitness for open repair, co-existing common iliac aneurysm, neck and aneurysm size, arterial angulations, aneurysm classification, endograft oversizing >or=15%, and type of stent-graft, the presence of IPS was not associated with significantly higher rates of aortic neck dilatation (30.6% versus 38.0%, p>0.05) and did not influence cumulative rates of type I endoleak, endovascular reintervention, or conversion to open surgery (p>0.05). Similarly, the presence of DM did not influence the above-mentioned study endpoints. CONCLUSION: In contrast to observations regarding the natural course of AAAs, impaired pulmonary status does not negatively influence aortic neck dilatation, while the presence of diabetes does not protect from these dismal events after EVAR.

Treatment of joint prosthesis infection in accordance with current recommendations improves outcome

BACKGROUND: Recently recommended treatment modalities for prosthetic joint infection (PJI) were evaluated. METHODS: A retrospective cohort analysis of 68 patients with PJI of hip or knee who were treated from 1995 through 2004 was conducted at the University Hospital Bern (Bern, Switzerland). RESULTS: A 2-stage exchange was the most frequent (75.0%) surgical strategy, followed by retention and debridement (17.6%), 1-stage exchange (5.9%), and resection arthroplasty or suppressive antimicrobial treatment (1.5%). The chosen strategy was in 88% agreement with the recommendations. Adherence was only 17% for retention and debridement and was 0% for 1-stage exchange. Most PJIs (84%) were treated with an adequate or partially adequate antimicrobial regimen. Recurrence-free survival was observed in 51.5% of PJI episodes after 24 months of follow-up. The risk of treatment failure was significantly higher for PJI treated with a surgical strategy other than that recommended (hazard ratio, 2.34; 95% confidence interval, 1.10-4.70; P = .01) and for PJIs treated with antibiotics not corresponding to recommendations (hazard ratio, 3.45; confidence interval, 1.50-7.60; P = .002). Other risk factors associated with lack of healing were a high infection score at the time of diagnosis (hazard ratio, 1.29; 95% confidence interval, 1.10-1.40; P < .001) and presence of a sinus tract (hazard ratio, 2.35; 95% confidence interval, 1.10-5.0; P = .02). CONCLUSIONS: Our study demonstrates the value of current treatment recommendations. Inappropriate choice of conservative surgical strategies (such as debridement and retention) and inadequate antibiotic treatment are associated with failure.