For the clarification of the immaturity of overall survival, the analysis was done when the number of events required to provide 80% power to the primary analysis (progression-free survival) was ...reached. To respond to Sütcüoğlu and colleagues’ concerns about the effect of surgery and maintenance treatment on results, we did a Cox regression analysis that included the following variables: surgery as a time-dependent covariate, treatment group, and stratification factors. Because the toxicity was as expected, we reproduced the same schedule in the phase 3 study.1 In response to Sasi and colleagues, we agree with their remarks, but sarcomas are heterogenous diseases with different responses to therapies, different evolutions even when metastatic, and some patients, even with metastatic disease, could have a curative intent to their treatment for these particular diseases (eg, young patient with oligometastatic disease); hence, a small decrease in their quality of life, lasting about 5 months with doxorubicin combination treatment, could be acceptable.
The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. ...Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.
We investigated a series of 29 newly ...diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.
All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival.
Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies.
Objective To determine the efficacy of 16 hour nicotine patches among pregnant smokers, with the dose individually adjusted according to saliva cotinine levels (potential range 10-30 mg/day). Design ...Randomised, double blind, placebo controlled, parallel group, multicentre trial (Study of Nicotine Patch in Pregnancy, SNIPP) between October 2007 and January 2013. Setting 23 maternity wards in France. Participants 476 pregnant smokers aged more than 18 years and between 12 and 20 weeks’ gestation, who smoked at least five cigarettes a day. After exclusions, 402 women were randomised: 203 to nicotine patches and 199 to placebo patches. Data were available on 192 live births in each group. Interventions Nicotine and identical placebo patches were administered from quit day up to the time of delivery. Doses were adjusted to saliva cotinine levels when smoking to yield a substitution rate of 100%. Participants were assessed monthly and received behavioural smoking cessation support. Main outcome measures The primary outcomes were complete abstinence (self report confirmed by carbon monoxide level in expired air ≤8 ppm) from quit date to delivery, and birth weight. The secondary outcomes were point prevalence of abstinence, time to lapse (a few puffs) or relapse, and delivery and birth characteristics. All data were analysed on an intention to treat basis. Results Complete abstinence was achieved by 5.5% (n=11) of women in the nicotine patch group and 5.1% (n=10) in the placebo patch group (odds ratio 1.08, 95% confidence interval 0.45 to 2.60). The median time to the first cigarette smoked after target quit day was 15 days in both groups (interquartile range 13-18 in the nicotine patch group, 13-20 in the placebo patch group). The point prevalence abstinence ranged from 8% to 12.5% in the nicotine patch group and 8% to 9.5% in the placebo patch group without statistically significant differences. The nicotine substitution rate did not differ from 100%, and the self reported median compliance rate was 85% (interquartile range 56-99%) in the nicotine patch group and 83% (56-95%) in the placebo patch group, assessed at 1016 visits. The mean birth weight was 3065 g (SE 44 g) in the nicotine patch group and 3015 g (SE 44 g) in the placebo patch group (P=0.41). Diastolic blood pressure was significantly higher in the nicotine patch group than in the placebo patch group. The frequency of serious adverse events was similar between the groups, although more non-serious adverse reactions, mainly of skin, occurred in the nicotine patch group. Conclusion The nicotine patch did not increase either smoking cessation rates or birth weights despite adjustment of nicotine dose to match levels attained when smoking, and higher than usual doses. Trial registration ClinicalTrials.gov NCT00507975.
Background
The long‐term survival of germline retinoblastoma patients is decreased due to the risk of second primary tumors (SPTs) that occur years after the diagnosis of retinoblastoma. This risk is ...related to genetic predisposition and other factors, such as the treatment of retinoblastoma by external beam radiotherapy (EBRT).
Procedure
We studied the incidence, risk factors, and prognosis of specific craniofacial SPTs developed within the margins of radiation field in a cohort of 209 patients with germline retinoblastoma treated with EBRT at our institution between 1977 and 2010. Clinical characteristics, survival, incidence, and histology of craniofacial SPTs were recorded.
Results
Fifty‐three of the 209 patients developed 60 distinct craniofacial SPTs in irradiated field with a median time from EBRT of 16.9 years (4‐35) and a median follow‐up of 24.8 years (5.3‐40). Osteosarcoma (33.3%) and undifferentiated sarcoma (23.3%) were the more prevalent histological entities. Benign tumors (16.7%) also occurred. The cumulative incidence of craniofacial SPTs reached 32.6% at 35 years after EBRT, and the median survival after diagnosis was five years. In our series, irradiation under 12 months of age, bilateral EBRT, or previous treatment of retinoblastoma with chemotherapy did not significantly increase the risk of craniofacial SPTs.
Conclusions
This work presents a strong argument to avoid EBRT in the management of retinoblastoma and emphasizes the high risk and poor prognosis of specific craniofacial SPTs. This study also points to the question of the need and benefits of special programs for early detection of craniofacial SPTs in survivors of irradiated germline retinoblastoma.
The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this ...population was undertaken.
Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition.
Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS ≥ 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03).
Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter.
Abstract Introduction We aimed to confirm the diagnostic value and to evaluate the pre- and post-therapeutic prognostic value of cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and ...IL-6 in patients with diffuse large B-cell primary central nervous system lymphoma (PCNSL). Patients and methods IL-10 and IL-6 concentrations were measured in 79 patients with PCNSL at diagnosis and in 40 control individuals. Fifty-four PCNSL patients underwent repeat assessments starting at diagnosis. Results The IL-10 concentration distinguished PCNSL from other neurologic diseases with a sensitivity of 88.6% and a specificity of 88.9% with a cutoff of 4 pg/ml. In a multivariate analysis of PCNSL patients, CSF involvement was associated with a higher IL-10 concentration (mean log (IL-10) of 4.4 versus 2.5 pg/ml, respectively, p = 0.0004). The pre-therapeutic IL-10 concentration had no prognostic impact on outcome. The IL-10 concentration decreased after treatment for most patients tested. Among patients with complete remission or partial remission, as evaluated by magnetic resonance imaging (MRI), a persistent detectable IL-10 level in the CSF at the end of treatment was associated with a negative impact on progression-free survival (PFS) (1-year PFS: 15%, 95% confidence interval CI: 2.5–38% versus 59%, 95% CI: 32–78%, respectively, p = 0.0004). Conclusion Our study confirmed that IL-10 is a useful biomarker for the diagnosis of PCNSL. We highlight new findings showing that the IL-10 level in the CSF could be used as a surrogate marker for CSF involvement and that the post-treatment IL-10 concentration could complement standard MRI for therapeutic response assessment in PCNSL.
Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory ...failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis.
Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). In this ...prospective study, we report here the prognostic impact of pTKa in ER+/HER2- MBC patients treated with endocrine therapy and CDK4/6 inhibitor.
Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2- MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden).
From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0-14). Median follow-up was 13.8 months (range 6-31), with median PFS and OS of 9.6 months (95%CI 7.0-11.3) and 28 months (95%CI 23-not reached), respectively. Median baseline pTKa was 292 Du/L (range 20-27,312 Du/L, IQR 89-853). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI 1.1-1.4, p = 0.0005) and OS (HR = 1.3 95%CI 1.2-1.6, p < 0.0001), and 4-week pTKa was associated with OS (HR = 1.6 95%CI 1.3-2, p < 0.0001). That survival prediction was significantly improved by the addition of baseline pTKa to clinicopathological characteristics. Adding pTKa changes at 4 weeks to baseline pTKa did not further increase survival prediction.
This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2- MBC patients treated with endocrine therapy and palbociclib.
Purpose: To assess the seizure‐freedom rates and self‐perceived psychosocial changes associated with the long‐term outcome of epilepsy surgery in patients with refractory medial temporal lobe ...epilepsy associated with hippocampal sclerosis.
Methods: A standard questionnaire was given to 183 patients who underwent surgery between 1988 and 2004, and 110 were completed.
Results: The mean duration of follow‐up after surgery was 7 years, with a maximum of 17 years. The probability that patients were seizure‐free after surgery was dependent on the definition of the seizure freedom. For the patients who were seizure‐free since surgery (Engel's class Ia), the probability was 97.6% at 1 year after surgery, 85.2% at 2 years after surgery, 59.5% at 5 years after surgery, and 42.6% at 10 years after surgery. For the patients who still experienced rare disabling seizures after surgery but were seizure‐free at least 1 year before the time of assessment, the probability was of 97.6% at 1 year after surgery, 95% at 2 years after surgery, 82.8% at 5 years after surgery, and 71.1% at 10 years after surgery.
The psychosocial long‐term outcome, as measured by indices of driving, employment, familial and social relationships, and marital status, was similar to the psychosocial short‐term outcome. It did not depend on seizure freedom or on follow‐up time interval and was not influenced statistically by seizure frequency in cases of persisting seizures. Most but not all patients noticed a substantial overall improvement in their psychosocial condition; 48% drove (increased by 7%), 47% improved (14% worsened) in their employment status, and 68% improved (5% worsened) in their familial and social relationships. Overall, 91% of patients were satisfied with the surgery, and 92% did not regret their decision.
Conclusions: The results of this study suggest that temporal lobe surgery has real long‐term benefits. Two specific conclusions emerge: (a) the long‐term rates of freedom from seizure depend on how seizure freedom is defined, and (b) the psychosocial long‐term outcome does not change dramatically over years and does not depend on seizure freedom.
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