RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their ...relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first‐and/or second‐line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non‐responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast‐enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long‐acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first‐line (53.5%) or second‐line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06–3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy.
Clinical Trial Registration
Registered at CNIL‐CERB, Assistance publique hopitaux de Paris as “E‐NETNET‐L‐E‐CT” July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.
A European study of liver metastases with CT in 14 expert centers in NET treatment has shown that a ≥10% decrease in size of three liver metastases could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in liver metastases CT‐density were not predictive of treatment efficacy.
We describe a simple iterative approach to augment TCR affinity, which we studied using a myelin oligodendrocyte glycoprotein-specific TCR. We hypothesized that single amino acid modifications in TCR ...CDR3 could enhance TCR sensitivity through focal interactions with antigenic peptide while minimizing the risk of cross-reactivity observed previously in TCR more broadly mutagenized using in vitro evolution techniques. We show that this iterative method can indeed generate TCR with Ag sensitivity 100-fold greater than the parental receptor and can endow TCR with coreceptor independence. However, we also find that single amino acid mutations in the CDR3 can alter TCR fine specificity, affecting recognition requirements for Ag residues over most of the length of the MHC binding groove. Furthermore, minimal changes in surface-exposed CDR3 amino acids, even the addition of a single hydroxyl group or conversion of a methyl or sulfhydryl moiety to a hydroxyl, can confer modified Ag-specific TCR with new self-reactivity. In vivo modeling of modified TCR through retroviral TCR gene transfer into Rag(-/-) mice confirmed the biological significance of these altered reactivities, although it also demonstrated the feasibility of producing Ag-specific, positively selecting, coreceptor-independent receptors with markedly increased Ag sensitivity. These results affirm the possibility of readily generating affinity-enhanced TCR for therapeutic purposes but demonstrate that minimal changes in TCR CDR3 structure can promote self reactivity and thereby emphasize the importance of caution in validating receptors with even subtle alterations before clinical application.
Radiation therapy (RT) is an important component of breast cancer treatment that reduces local recurrence and improves survival after breast conservation. Breast conservation rates have increased ...significantly since the late 1980s and techniques have improved with greater awareness of the impact of radiation on the heart. An overview of randomized controlled trials of breast conservation using standard whole breast irradiation, whole breast hypofractionation, accelerated partial breast irradiation (APBI) and intraoperative radiation are reviewed. Selection criteria for breast conservation and the utility of adding a boost dose to the primary tumor site are reviewed. Modern dose constraints are documented and 10 different radiation techniques from the 1980s through to modern volumetric modulated arc therapy (VMAT) are compared for a patient where the breast and internal mammary nodes are treated. A radiation boost reduces the risk of a recurrence for most, but not all patients. Short courses of RT over 3-4 weeks are generally as effective as longer courses. Short-term follow-up of trials of APBI show promise for selected good prognosis subgroups. The role of intraoperative radiation remains controversial. In the last 30 years, there have been significant advances in radiation techniques. Modern radiotherapy equipment and techniques will reduce complications and improve survival rates.
Aim
The aim of this study was to examine the impact of dystonia aetiology and duration, contracture, and age at deep brain stimulation (DBS) surgery on outcome in a cohort of children with medically ...refractory, disabling primary, secondary‐static, or secondary‐progressive dystonias, including neurodegeneration with brain iron accumulation (NBIA).
Method
Dystonia severity was assessed using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) motor score at baseline and 6 and 12 months postoperatively in a cohort of 70 consecutive children undergoing DBS between June 2005 and July 2011.
Results
Two children (3%) received unilateral DBS for hemidystonia and were excluded and five (7%) developed infections requiring part‐DBS removal within 6 months, leaving 63 children (90%) undergoing bilateral DBS for follow‐up (34 males, 29 females; mean age at surgery for the whole group 10y 4mo, SD 4y 2mo, range 1–14y). Seventeen children were classified with primary dystonia: mean age 12 years 11 months, SD 4 years 6 months range 4 years 6 months to 17 years 3 months; 28 as having secondary‐static dystonia: mean age 10 years 2 months, SD 4 years 9 months (range 3y 3mo–20y); five as having secondary‐progressive dystonia: mean age 8 years 11 months, SD 3 years 9 months (range 5y 5mo–13y 1mo); and 13 as having NBIA dystonia: mean age 10 years 2 months, SD 3 years 11 months (range 1–14y). Children with primary dystonias demonstrated greater improvements in BFMDRS motor score than those in the other aetiological categories (Kruskal–Wallis test, p<0.001), which correlated negatively with dystonia duration and more strongly still against the ratio of dystonia duration normalized to age at surgery (DD/AS ratio) at 1 year (Spearman's rank correlation coefficient 0.4752 and −0.599 respectively). A similar significant negative correlation was found in the secondary‐static dystonia group between outcome at 1 year and DD/AS ratio (−0.461). Poorer outcome in secondary dystonia coincided with the absence of a period of normal motor development in comparison with the primary dystonia group. A significant improvement in BFMDRS motor score was seen in the NBIA group at 6, but not 12 months (Wilcoxon signed rank test p=0.028, p=0.85 respectively). No reduction in efficacy was seen in children with a musculoskeletal deformity at the time of surgery.
Conclusion
Response to pallidal DBS in the treatment of dystonia declines with the proportion of life lived with dystonia in primary and secondary dystonia. Other intrinsic factors reduce the median magnitude of reduction in secondary dystonia after DBS. DBS should be offered early, preferably within 5 years of onset, to maximize benefits and reduce the childhood experience of dystonia, including musculoskeletal deformity. Other multidimensional assessments are required to understand how DBS improves the lives of children with dystonia.
This article is commented on by Monbaliu et al on pages 495–496 of this issue.
Aim
Hyperkinetic movement disorders (HMDs) can be assessed using impairment‐based scales or functional classifications. The Burke–Fahn–Marsden Dystonia Rating Scale‐movement (BFM‐M) evaluates ...dystonia impairment, but may not reflect functional ability. The Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) are widely used in the literature on cerebral palsy to classify functional ability, but not in childhood movement disorders. We explore the concordance of these three functional scales in a large sample of paediatric HMDs and the impact of dystonia severity on these scales.
Method
Children with HMDs (n=161; median age 10y 3mo, range 2y 6mo–21y) were assessed using the BFM‐M, GMFCS, MACS, and CFCS from 2007 to 2013. This cross‐sectional study contrasts the information provided by these scales.
Results
All four scales were strongly associated (all Spearman's rank correlation coefficient rs>0.72, p<0.001), with worse dystonia severity implying worse function. Secondary dystonias had worse dystonia and less function than primary dystonias (p<0.001). A longer proportion of life lived with dystonia is associated with more severe dystonia (rs=0.42, p<0.001).
Interpretation
The BFM‐M is strongly linked with the GMFCS, MACS, and CFCS, irrespective of aetiology. Each scale offers interrelated but complementary information and is applicable to all aetiologies. Movement disorders including cerebral palsy can be effectively evaluated using these scales.
What this paper adds
Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System are strongly associated in hyperkinetic movement disorders.
Dystonia impairment shows strong association with all three functional scales.
The scales' relationships are consistent for cerebral palsy and non‐cerebral palsy aetiologies.
All aetiological groups share common patterns of impairment and function.
Secondary dystonias have greater impairment and lower functional ability than primary dystonias.
This article is commented on by Himmelmann on page 113 of this issue.
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There is a limited amount of research that examines social-emotional functioning in children with Fetal Alcohol Spectrum Disorder (FASD), and the majority of it relies on parent and teacher reports ...of social impairments. Because these provide broad measures of social function, they fail to elucidate the underlying specific skills with which this group of children has difficulty. The current study examines emotion-recognition abilities in children with FASD, as it plays a central role in social interaction. Participants were 22 children with diagnosed FASD (ages 8-14), and age- and gender-matched typically developing controls. Tasks included measures of emotion recognition from three nonlinguistic modalities: facial expressions, emotional tone of voice, and body positioning and movement. Participant's parents completed measures of adaptive and behavioral function that were related to children's performance on aspects of emotion recognition. Overall, the results show that children with FASD have more difficulties with emotion recognition than typically developing age-matched peers, but these difficulties may not be clinically significant (e.g., smaller effect size) or may be specific to the age of the individual exhibiting the emotion (i.e., child vs. adult). These results are discussed in the context of previous studies.
Background
The finite life of non-rechargeable batteries powering implantable pulse generators (IPG) necessitates their periodic replacement. Children receiving deep brain stimulation (DBS) may ...require frequent battery changes over their treatment lifetime.
Objectives
We aimed to determine the battery life of IPGs used in pallidal DBS for the treatment of dystonia in children and young people.
Methods
We make use of a review of case notes of all children and young people undergoing DBS surgery at our institution from June 2005 to May 2010.
Results
A total of 54 children and young people underwent surgery on at least one occasion, with a total of 76 IPGs implanted. Replacement IPGs due to battery failure were required in 15 out of 54 (27.8%). The average time to battery failure was 24.5 ± 2.9 months (95% confidence interval), with a range of 13–39 months. Battery life was significantly longer in primary compared to subsequent IPGs. No difference in longevity was seen between different IPG devices.
Conclusions
IPG battery life may be short in children and young people receiving treatment for dystonia. These findings highlight the potential benefits of the recently introduced rechargeable neurostimulators.
Early onset dystonia (dyskinesia) and deafness in childhood pose significant challenges for children and carers and are the cause of multiple disability. It is particularly tragic when the child ...cannot make use of early cochlear implantation (CI) technology to relieve deafness and improve language and communication, because severe cervical and truncal dystonia brushes off the magnetic amplifier behind the ears. Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) neuromodulation can reduce dyskinesia, thus supporting CI neuromodulation success.
We describe the importance of the order of dual neuromodulation surgery for dystonia and deafness. First with bilateral GPi DBS using a rechargeable ACTIVA-RC neurostimulator followed 5 months later by unilateral CI with a Harmony (BTE) Advanced Bionics Hi Res 90 K cochlear device. This double neuromodulation was performed in series in a 12.5 kg 5 year-old ex-24 week gestation-born twin without a cerebellum.
Relief of dyskinesia enabled continuous use of the CI amplifier. Language understanding and communication improved. Dystonic storms abated. Tolerance of sitting increased with emergence of manual function. Status dystonicus ensued 10 days after ACTIVA-RC removal for infection-erosion at 3 years and 10 months. He required intensive care and DBS re-implantation 3 weeks later together with 8 months of hospital care. Today he is virtually back to the level of functioning before the DBS removal in 2012 and background medication continues to be slowly weaned.
This case illustrates that early neuromodulation with DBS for dystonic cerebral palsy followed by CI for deafness is beneficial. Both should be considered early i.e. under the age of five years. The DBS should precede the CI to maximise dystonia reduction and thus benefits from CI. This requires close working between the paediatric DBS and CI services.
•This is the first description of a rechargeable neurostimulator for deep brain stimulation (DBS) implantation implanted in a 5-year old ex-24 week preterm boy to relieve dystonic-choreoathetosis allowing subsequent cochlear implantation (CI) 5 months later.•The technical challenges of dual DBS and CI are described.•The benefits of DBS in reducing dystonia storms are described.•The benefits of dual DBS and CI for hearing and language are described.
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