Defining disease status in gastroenteropancreatic neuroendocrine tumors: Choi-criteria or RECIST?

PURPOSE: Adequate monitoring of changes in tumor load is fundamental for the assessment of the course of disease and response to treatment. There is an ongoing debate on the utility of RECIST v1.1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: In this retrospective real-life cohort study, Choi-criteria were compared with RECIST v1.1. The agreement between both criteria and the association with survival endpoints were evaluated. RESULTS: Seventy-five patients were included with a median follow-up of 35 months (range 8-53). Median progression-free survival (mPFS) according to RECIST v1.1 was 15 months (range 2-50) compared to 14 months (range 2-50) in Choi. According to RECIST, 33 (44%) patients were classified as having stable disease (SD), 40 (53%) as progressive disease (PD) and two (3%) patients as partial response (PR), compared to 9 (12%) patients classified as SD, 50 (67%) as PD and 16 (21%) as PR according to Choi-criteria. Overall concordance between the criteria was moderate (Cohen's Kappa = 0.408, p < 0.001) and agreement varied between 57 and 69% at each consecutive scan (p < 0.001). Survival analysis showed significant differences in overall survival (OS) for RECIST v1.1 categories PD and non-PD (log-rank p = 0.02), however, in Choi no significant differences in OS were found (p = 0.27). CONCLUSION: RECIST v1.1 had a better clinical utility and prognostic value compared to Choi-criteria. Still, RECIST were also not sufficient to adequately predict OS. This outlines the need for new tools that provides accurate information on the disease course and treatment response to support precise prognostication in patients with GEP-NETs.

Quality of life after esophageal replacement in children.

PURPOSE: Assessing quality of life (QoL) after esophageal replacement (ER) for long gap esophageal atresia (LGEA). METHODS: All patients after ER for LGEA with gastric pull-up (GPU n = 9) or jejunum interposition (JI n = 14) at the University Medical Center Groningen and Utrecht (1985-2007) were included. QoL was assessed with 1) gastrointestinal-related QoL using the Gastrointestinal Quality of Life Index (GIQLI)), 2) general QoL (Child Health questionnaire CHF87-BREF (children)/World Health Organization questionnaire WHOQOL-BREF (adults)), and 3) health-related QoL (HRQoL) (TNO AZL TACQoL/TAAQoL). Association of morbidity (heartburn, dysphagia, dyspnea on exertion, recurrent cough) and (HR)QoL was evaluated. RESULTS: Six patients after GPU (75%) and eight patients after JI (57%) responded to the questionnaires (mean age 15.7, SD 5.9, 12 male, two female). Mean gastrointestinal, general and health-related QoL total scores of the patients were comparable to healthy controls. However, young adults reported a worse physical functioning (p = 0.02) but better social functioning compared to peers (p = 0.01). Morbidity was not associated with significant differences in (HR)QoL. CONCLUSIONS: With the current validated QoL most patients after ER with GPU and JI for LGEA have normal generic and disease specific QoL scores. Postoperative morbidity does not seem to influence (HR)QoL. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: III.

Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice.

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials.

Predictive Role of F2-Isoprostanes as Biomarkers for Brain Damage after Neonatal Surgery.

OBJECTIVE: Neonates have a high risk of oxidative stress during anesthetic procedures. The predictive role of oxidative stress biomarkers on the occurrence of brain injury in the perioperative period has not been reported before. METHODS: A prospective cohort study of patients requiring major surgery in the neonatal period was conducted. Biomarker levels of nonprotein-bound iron (NPBI) in plasma and F2-isoprostane in plasma and urine before and after surgical intervention were determined. Brain injury was assessed using postoperative MRI. RESULTS: In total, 61 neonates were included, median gestational age at 39 weeks (range 31-42) and weight at 3000 grams (1400-4400). Mild to moderate brain lesions were found in 66%. Logistic regression analysis showed a significant difference between plasma NPBI in patients with nonparenchymal injury versus no brain injury: 1.34 umol/L was identified as correlation threshold for nonparenchymal injury (sensitivity 67%, specificity 91%). In the multivariable analysis, correcting for GA, no other significant relation was found with the oxidative stress biomarkers and risk factors. CONCLUSION: Oxidative stress seems to occur during anaesthesia in this cohort of neonates. Plasma nonprotein-bound iron showed to be associated with nonparenchymal injury after surgery, with values of 1.34 umol/L or higher. Risk factors should be elucidated in a more homogeneous patient group.

Ocular stability and set-point adaptation.

A fundamental challenge to the brain is how to prevent intrusive movements when quiet is needed. Unwanted limb movements such as tremor impair fine motor control and unwanted eye drifts such as nystagmus impair vision. A stable platform is also necessary to launch accurate movements. Accordingly, nature has designed control systems with agonist (excitation) and antagonist (inhibition) muscle pairs functioning in push-pull, around a steady level of balanced tonic activity, the set-point Sensory information can be organized similarly, as in the vestibulo-ocular reflex, which generates eye movements that compensate for head movements. The semicircular canals, working in coplanar pairs, one in each labyrinth, are reciprocally excited and inhibited as they transduce head rotations. The relative change in activity is relayed to the vestibular nuclei, which operate around a set-point of stable balanced activity. When a pathological imbalance occurs, producing unwanted nystagmus without head movement, an adaptive mechanism restores the proper set-point and eliminates the nystagmus. Here we used 90 min of continuous 7 T magnetic field labyrinthine stimulation (MVS) in normal humans to produce sustained nystagmus simulating vestibular imbalance. We identified multiple time-scale processes towards a new zero set-point showing that MVS is an excellent paradigm to investigate the neurobiology of set-point adaptation.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.

Effects and efficacy of laparoscopic fundoplication in children with GERD: a prospective, multicenter study.

INTRODUCTION: Laparoscopic antireflux surgery (LARS) in children primarily aims to decrease reflux events and reduce reflux symptoms in children with therapy-resistant gastroesophageal reflux disease (GERD). The aim was to objectively assess the effect and efficacy of LARS in pediatric GERD patients and to identify parameters associated with failure of LARS. METHODS: Twenty-five children with GERD [12 males, median age 6 (2-18) years] were included prospectively. Reflux-specific questionnaires, stationary manometry, 24-h multichannel intraluminal impedance pH monitoring (MII-pH monitoring) and a 13C-labeled Na-octanoate breath test were used for clinical assessment before and 3 months after LARS. RESULTS: After LARS, three of 25 patients had persisting/recurrent reflux symptoms (one also had persistent pathological acid exposure on MII-pH monitoring). New-onset dysphagia was present in three patients after LARS. Total acid exposure time (AET) (8.5-0.8 %; p < 0.0001) and total number of reflux episodes (p < 0.001) significantly decreased and lower esophageal sphincter (LES) resting pressure significantly increased (10-24 mmHg, p < 0.0001) after LARS. LES relaxation, peristaltic contractions and gastric emptying time did not change. The total number of reflux episodes on MII-pH monitoring before LARS was a significant predictor for the effect of the procedure on reflux reduction (p < 0.0001). CONCLUSIONS: In children with therapy-resistant GERD, LARS significantly reduces reflux symptoms, total acid exposure time (AET) and number of acidic as well as weakly acidic reflux episodes. LES resting pressure increases after LARS, but esophageal function and gastric emptying are not affected. LARS showed better reflux reduction in children with a higher number of reflux episodes on preoperative MII-pH monitoring.

Eye movements in vestibular disorders.

The differential diagnosis of patients with vestibular symptoms usually begins with the question: is the lesion central or is it peripheral? The answer commonly emerges from a careful examination of eye movements, especially when the lesion is located in otherwise clinically silent areas of the brain such as the vestibular portions of the cerebellum (flocculus, paraflocculus which is called the tonsils in humans, nodulus, and uvula) and the vestibular nuclei as well as immediately adjacent areas (the perihypoglossal nuclei and the paramedian nuclei and tracts). The neural circuitry that controls vestibular eye movements is intertwined with a larger network within the brainstem and cerebellum that also controls other types of conjugate eye movements. These include saccades and pursuit as well as the mechanisms that enable steady fixation, both straight ahead and in eccentric gaze positions. Navigating through this complex network requires a thorough knowledge about all classes of eye movements to help localize lesions causing a vestibular disorder. Here we review the different classes of eye movements and how to examine them, and then describe common ocular motor findings associated with central vestibular lesions from both a topographic and functional perspective.

Impact of laparoscopic antireflux surgery on belching in pediatric GERD patients.

BACKGROUND: Laparoscopic antireflux surgery (LARS) is a well-established treatment option for children with proton pomp inhibitor (PPI)-resistant gastroesophageal reflux disease (GERD). Besides preventing reflux of gastric fluid and solid content, LARS may also impair the ability of the stomach to vent intragastric air (i.e. gastric belching) and induce gas-related complications, such as bloating and/or hyperflatulence. Furthermore, it was previously hypothesized that LARS induces a behavioral type of belching, not originating from the stomach, called supragastric belching. The aim of this study was to objectively evaluate the impact of LARS on gastric (GB) and supragastric belching (SGB) in children with GERD. METHODS: We performed a prospective, Dutch multicenter cohort study including 25 patients (12 males, median age 6 (range 2-18) years) with PPI-resistant GERD who were scheduled for LARS. Twenty-four-hour multichannel intraluminal impedance pH monitoring (MII-pH monitoring) was performed before and 3 months after fundoplication. Impedance pH tracings were analyzed for reflux episodes and GBs and SGBs. KEY RESULTS: LARS reduced acid exposure time from 8.5% (6.0-16.2%) to 0.8% (0.2-2.8%), p < 0.001. The number of GBs also significantly decreased after LARS (59 [43-77] VS 5 [2-12], p < 0.001). The number of air swallows remained unchanged after LARS. SGBs were infrequent before LARS with no change in the number of SGB observed after the procedure. Postoperative belching symptoms were associated with GBs, not with SGBs. CONCLUSION & INFERENCES: LARS significantly reduces the number of GBs in children with GERD, whereas the number of air swallows remains unchanged. Postoperative symptomatic belching is associated with GBs, but not with SGBs. These findings suggest that LARS does not induce the occurrence of SGBs in children, but longer follow-up is required.

Perioperative hospital mortality at a tertiary paediatric institution.

BACKGROUND: Research in postoperative mortality is scarce. Insight into mortality and cause of death might improve and innovate perioperative care. The objective for this study was to report the 24-hour and 30-day overall, and surgery and anaesthesia-related, in-hospital mortality at a tertiary paediatric hospital. METHODS: All patients <18 yr old who underwent anaesthesia with or without surgery between January 1, 2006, and December 31, 2012, at the Wilhelmina Children's Hospital, Utrecht, The Netherlands, were included in this retrospective cohort study. Causes of death within 30 days were identified and tabulated into four major categories according to principal cause. RESULTS: A total of 45,182 anaesthetics were administered during this 7-yr period. The all-cause 24-hour hospital mortality was 13.1 per 10,000 anaesthetics (95% CI: 9.9-16.8) and the all-cause 30-day in-hospital mortality was 41.6 per 10,000 anaesthetics (95% CI: 35.9-48.0). In total five patients were partially contributable to anaesthesia (30-day mortality: 1.1/10,000, 95% CI: 0.4-2.6) and four patients were partially contributable to surgery (30-day mortality: 0.9/10,000, 95% CI: 0.2-2.3). Mortality was higher in neonates and infants, children with ASA physical status III and IV, and emergency- and cardiothoracic surgery. CONCLUSIONS: Neonates and infants, children with ASA physical status III or poorer, and emergency- and cardiothoracic surgery are associated with a higher postoperative mortality. Anaesthesia- or surgery-related complications contribute to mortality in only a small amount of the deaths, indicating the relative safety of paediatric surgical and anaesthetic procedures.

The cerebellum in eye movement control: nystagmus, coordinate frames and disconjugacy.

In this review we discuss several aspects of eye movement control in which the cerebellum is thought to have a key role, but have been relatively ignored. We will focus on the mechanisms underlying certain forms of cerebellar nystagmus, as well as the contributions of the cerebellum to binocular alignment in healthy and diseased states. A contemporary review of our understanding provides a basis for directions of further inquiry to address some of the uncertainties regarding the contributions of the cerebellum to ocular motor control.

Complete versus partial fundoplication in children with gastroesophageal reflux disease: results of a systematic review and meta-analysis.

Complete fundoplication (Nissen) has long been accepted as the gold standard surgical procedure in children with therapy-resistant gastroesophageal reflux disease (GERD); however, increasingly more evidence has become available for partial fundoplication as an alternative. The aim of this study was to perform a systematic review and meta-analysis comparing complete versus partial fundoplication in children with therapy-resistant GERD. PubMed (1960 to 2011), EMBASE (from 1980 to 2011), and the Cochrane Library (issue 3, 2011) were systematically searched according to the PRISMA statement. Results were pooled in meta-analyses and expressed as risk ratios (RRs). In total, eight original trials comparing complete to partial fundoplication were identified. Seven of these studies had a retrospective study design. Short-term (RR 0.64; p = 0.28) and long-term (RR 0.85; p = 0.42) postoperative reflux control was similar for complete and partial fundoplication. Complete fundoplication required significantly more endoscopic dilatations for severe dysphagia (RR 7.26; p = 0.007) than partial fundoplication. This systematic review and meta-analysis showed that reflux control is similar after both complete and partial fundoplication, while partial fundoplication significantly reduces the number of dilatations to treat severe dysphagia. However, because of the lack of a well-designed study, we have to be cautious in making definitive conclusions. To decide which type of fundoplication is the best practice in pediatric GERD patients, more randomized controlled trials comparing complete to partial fundoplication in children with GERD are warranted.

Continuous theta-burst stimulation of the right superior temporal gyrus impairs self-motion perception.

Sensory input from the semicircular canals (SCC) and otolith organs is centrally combined with signals from other sensory modalities to continuously update the internal estimate of self-motion. Constant velocity vertical on-axis rotation leads to decay of the nystagmus response from the horizontal SCC and of perceived angular velocity (PAV), and when the rotation stops, a similar oppositely directed post-rotatory response occurs. Case reports and electrical stimulation studies suggest an involvement of the temporo-peri-Sylvian vestibular cortex in generating the PAV. Here, we transiently inhibited the right superior temporal gyrus (STG) by use of continuous theta-burst stimulation (cTBS) and predicted an accelerated decay of PAV compared to controls (n = 5 control session first, n = 1 cTBS session first). Constant velocity (100°/s) vertical on-axis rotations were applied over 75 s before (1 block) and after (3 blocks) cTBS over the right STG in six subjects. Breaks between the rotations (75 s) were initiated by abrupt stops. By use of a rotating potentiometer, subjects indicated the PAV during and after the chair rotations. Simultaneously eye positions were recorded using a scleral search coil. One subject was excluded for per-rotary analysis. Early after cTBS, the post-rotary PAV decay time constant (DTC) was significantly (9.4 ± 5.7 vs. 13.6 ± 5.9 s; p = 0.049) reduced (no directionality to this effect observed). Overall, post-rotary PAV showed a trend toward shortened DTC compared to the control trials (p = 0.086) in the first 25 min after cTBS, while per-rotary PAV was not significantly changed. Per-rotary and post-rotary aVOR DTC were not significantly changed after cTBS (p > 0.05). These findings support the hypothesis that the right STG is involved in mediating self-motion perception and can be modulated by cTBS.

Multiplanar reconstruction computed tomography for diagnosis of scaphoid waist fracture union: a prospective cohort analysis of accuracy and precision.

OBJECTIVE: To examine reliability and validity concerning union of scaphoid fractures determined by multiplanar reconstruction computed tomography randomized at 6, 12, and 24 weeks after injury. MATERIALS AND METHODS: We used Fleiss' kappa to measure the opinions of three observers reviewing 44 sets of computed tomographic scans of 44 conservatively treated scaphoid waist fractures. We calculated kappa for the extent of consolidation (0-24 %, 25-49 %, 50-74 %, or 75-100 %) on the transverse, sagittal and coronal views. We also calculated kappa for no union, partial union, and union, and grouped the results for 6, 12, and 24 weeks after injury. As the reference standard for union, CT scans were performed at a minimum of 6 months after injury to determine validity. RESULTS: Overall inter-observer agreement was found to be moderate (κ = 0.576). No union (κ = 0.791), partial union (κ = 0.502), and union (κ = 0.683) showed substantial, moderate, and substantial agreement, respectively. The average sensitivity of multiplanar reconstruction CT for diagnosing union of scaphoid waist fractures was 73 %. The average specificity was 80 %. CONCLUSIONS: Our results suggest that multiplanar reconstruction computed tomography is a reliable and accurate method for diagnosing union or nonunion of scaphoid fractures. However, inter-observer agreement was lower with respect to partial union.

How stable is perceived direction of gravity over extended periods in darkness?

Previous studies reported linear drift of perceived vertical for brief (≤10 min) observation periods. Here, we repeated estimates of direction of gravity up to 60 min to evaluate whether the drift is sustained, shows saturation or even reverses over time. Fifteen healthy human subjects repetitively adjusted a luminous line along subjective visual vertical (SVV) and horizontal (SVH) over periods of 5 min (constituting one block). We obtained seven blocks within 60 min in each subject for SVV and SVH. In between the first six blocks, subjects remained in darkness for 5 min each, whereas the lights were briefly turned on before block 7. We noted significantly (p < 0.05) increased errors in perceived direction of gravity by block 2 (SVV) and 3 (SVH). These increases disappeared after turning on the lights before block 7. Focusing on blocks 2-6, significant drift started from similar offset positions and pointed to the same direction in a majority of runs in 9/15 (SVV) and 11/15 (SVH) subjects. When pooling data from all blocks, orthogonality of errors was lost in all subjects. Trial-to-trial variability remained stable over the seven runs for SVV and SVH. Only when pooling all runs, precision was significantly (p < 0.05) higher for the SVH. Our findings suggest that perceived direction of gravity continues to fluctuate over extended recording periods with individuals showing unique patterns of direction-specific drift while variability remains stable. As subjects were upright during the entire experiment and as drift persisted over several blocks, sensory adaptation seems unlikely. We therefore favor a central origin of this kind of drift.

The bedside examination of the vestibulo-ocular reflex (VOR): an update.

Diagnosing dizzy patients remains a daunting challenge to the clinician in spite of modern imaging and increasingly sophisticated electrophysiological testing. Here we review the major bedside tests of the vestibulo-ocular reflex and how, when combined with a proper examination of the other eye movement systems, one can arrive at an accurate vestibular diagnosis.

Is complete surgical resection of stage 4 neuroblastoma a prerequisite for optimal survival or may >95 % tumour resection suffice?

Numerous studies have shown that for optimal survival in localized International Neuroblastoma Staging System stage 1-3 neuroblastoma, complete tumour resection (CR, macroscopic total tumour removal) is usually mandatory. In contrast, it is conceivable that in stage 4 disseminated disease, less extensive surgery [gross total resection (GTR), >95 % tumour removal] may suffice. This review shows substantial survival benefit in studies reporting on stage 4 patients undergoing CR, but also in studies reporting on patients undergoing GTR. Comparison between these studies is severely hampered by treatment heterogeneity. We found only four studies that explicitly compared survival between patients undergoing either CR or GTR. Two of these studies showed favourable results for patients treated with CR, while the other two did not show differences in survival.

Temporal constancy of perceived direction of gravity assessed by visual line adjustments.

Here we investigated how well internal estimates of direction of gravity are preserved over time and if the subjective visual vertical (SVV) and horizontal (SVH) can be used inter-changeably. Fourteen human subjects repetitively aligned a luminous line to SVV, SVH or subjective visual oblique (± 45°) over 5 min in otherwise complete darkness and also in dim light. Both accuracy (i.e., the degree of veracity as reflected by the median adjustment error) and precision (i.e., the degree of reproducability as reflected by the trial-to-trial variability) of adjustments along the principle axes were significantly higher than along the oblique axes. Orthogonality was only preserved in a minority of subjects. Adjustments were significantly different between SVV vs. SVH (7/14 subjects) and between ±45° vs. -45° (12/14) in darkness and in 6/14 and 14/14 subjects, respectively, in dim light. In darkness, significant drifts over 5min were observed in a majority of trials (33/56). Both accuracy and precision were higher if more time was taken to make the adjustment. These results introduce important caveats when interpreting studies related to graviception. The test re-test reliability of SVV and SVH can be influenced by drift of the internal estimate of gravity. Based on spectral density analysis we found a noise pattern consistent with 1/fß noise, indicating that at least part of the trial-to-trial dynamics observed in our experiments is due to the dependence of the serial adjustments over time. Furthermore, using results from the SVV and SVH inter-changeably may be misleading as many subjects do not show orthogonality. The poor fidelity of perceived ± 45° indicates that the brain has limited ability to estimate oblique angles.

Course of life into adulthood of patients with biliary atresia: the achievement of developmental milestones in a nationwide cohort.

PURPOSE: To investigate the course of life of young adults diagnosed with biliary atresia (BA) in infancy by comparing patients who did and did not underwent transplantation with an age-matched Dutch reference group. METHODS: All patients from the Dutch BA registry, aged >18 years, were invited to complete the course of life questionnaire. RESULTS: Forty patients participated (response = 74%). Twenty-five had not undergone transplantation; 15 had undergone orthotopic liver transplantation. One significant between-group difference was found, namely in substance use and gambling. BA patients who underwent transplantation reported less use than the reference group (p = .01, moderate effect size). Additional moderate effect sizes were found for differences in psychosexual and social development and antisocial behavior. Patients who underwent transplantation had lower scores than one or both other groups. CONCLUSIONS: Development of BA survivors who did not undergo transplantation seems not delayed, whereas that of transplanted patients does seem somewhat delayed. However, patients who underwent transplantation display less risk behavior. Larger samples are necessary to confirm these findings.