Summary Background The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. Methods In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I–III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0–2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m 2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m 2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov , number NCT00411138 . Findings Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9–85·6), 5-year overall survival was 81·4% (95% CI 77·2–85·8) with chemoradiotherapy versus 76·1% (71·6–80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51–0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5–80·7) versus 69·1% (63·8–73·8; HR 0·70 [0·52–0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3–26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4–34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55–0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0–2·1) in both groups (HR 0·99 [95% CI 0·06–15·90]; p=0·99), and isola...

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Six subtypes of autosomal recessive pontocerebellar hypoplasia (PCH) have been identified and the genetic basis of four of these (PCH1, PCH2, PCH4, and PCH6) is known. PCH6 is associated with cerebral atrophy and multiple but variable respiratory chain defects in muscle and has been reported in one consanguineous Sephardic Jewish family. It is caused by mutations in the RARS2 gene which encodes mitochondrial arginine-transfer RNA synthetase. Here we describe a female patient born to nonconsanguineous British parents. She presented in the neonatal period with increased respiratory rate, poor feeding and transiently elevated blood and CSF lactate levels. She went on to manifest profound developmental delay and severe microcephaly. Edema of the hands, feet, and face were suggestive of a PEHO-like condition (progressive encephalopathy, edema, hypsarrhythmia and optic atrophy), although optic atrophy and hypsarrhythmia were absent. Cranial MRI at age 14 months showed generalized cerebral atrophy, thinning of the pons and gross atrophy and flattening of the cerebellar hemispheres. Muscle biopsies on two occasions were normal with normal respiratory chain studies. Despite the absence of respiratory chain defects, the phenotype was felt to be consistent with PCH6 and indeed two novel pathogenic RARS2 mutations were identified. Ours is the second report of PCH6 due to RARS2 mutations and demonstrates that respiratory chain abnormalities are not obligatory, whereas some features of PEHO might be present.

OBJECTIVE -Low birth weight has been linked to an increased risk of type 2 diabetes and cardiovascular disease in adult life. The fetal insulin hypothesis proposed that a genetic predisposition to insulin resistance may also influence vascular development. Therefore, impaired vascular function may be an intrinsic abnormality in low-birth weight infants that antedates clinical features of the insulin resistance syndrome.RESEARCH DESIGN AND METHODS -Two groups of 3-month-old term infants were included in the study: 17 infants of lowest quartile birth weight (LQBW) and 21 infants of highest quartile birth weight (HQBW). Three aspects of skin microvascular function were examined; response to local heating, response to acetylcholine iontophoresis, and capillary density.RESULTS -Median (interquartile ranges) birth weights of the LQBW and HQBW infants were 3,140 g (2,738 -3,254) and 3,920 g (3,750 -4,020), respectively. Skin maximal hyperemic response to local heating was 2.14 V (1.68 -2.30) in the LQBW group vs. 2.44 V (1.96 -2.90) in the HQBW group (P ϭ 0.020), and the endothelium-dependent vasodilatory response was 1.03 V (0.62-1.32) in the LQBW group vs. 0.78 V (0.45-1.32) in the HQBW group (P ϭ 0.297). Capillary density in the LQBW and HQBW groups were 46.3 mm Ϫ2 (40.1-53.7) and 44.1 mm Ϫ2 (41.7-56.0), respectively (P ϭ 0.736).CONCLUSIONS -Skin maximal hyperemic response was lower in LQBW infants, although no reduction in capillary density or defect in endothelium-dependent vasodilatation was observed. Such a lower maximal hyperemic response in early life in LQBW subjects who are at risk for type 2 diabetes and cardiovascular disease supports the hypothesis that impaired microvascular function is an early antecedent to diabetes in later life. Diabetes Care 24:1102-1107, 2001R etrospective studies in the U.K. have shown that low birth weight is associated with the development of type 2 diabetes, hypertension, and increased cardiovascular mortality in adult life, which are clinical features of insulin resistance syndrome (1). This association is independent of social class and adult BMI and has been confirmed in studies conducted in other populations (2) and countries (3,4). Barker (5) proposed the fetal programming hypothesis to explain the association, stipulating that undernutrition in utero leads to impaired fetal growth, which may permanently program the structure and function of the pancreas, thus predisposing later development of type 2 diabetes. An alternative or complementary explanation is the fetal insulin hypothesis, which states that the same polygenic factors that increase insulin resistance in utero and in adult life produce two phenotypic expressions: an infant of low birth weight and an adult with an increased risk for diabetes and hypertension (6).In parallel with these observations has been the understanding that endothelial dysfunction is a crucial biological determinant of cardiovascular disease (7). Furthermore, impaired endotheliumdependent vasodilatation has been linked to key components of i...

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AIM We aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms. METHOD Retrospective review and brain MRI analysis of children enrolled in the InternationalCollaborative Infantile Spasms Study (ICISS) who developed a movement disorder on vigabatrin therapy. Comparisons were made with controls within ICISS who had no movement disorder. RESULTSTen of 124 infants had a movement disorder and in eight it had developed on vigabatrin therapy. Two had a movement disorder that resolved on dose-reduction of vigabatrin, one had improvement on withdrawing vigabatrin, two had resolution without any dose change, and in three it persisted despite vigabatrin withdrawal. The typical brain MRI changes associated with vigabatrin therapy were noted in two infants. Ten control infants were identified. Typical MRI changes noted with vigabatrin were noted in three controls.INTERPRETATION It is possible that in two out of eight cases, vigabatrin was associated with the development of a movement disorder. In six out of eight cases a causal relationship was less plausible. The majority of infants treated with vigabatrin did not develop a movement disorder. MRI changes associated with vigabatrin do not appear to be specifically related to the movement disorder.Infantile spasms are an age-related epileptic encephalopathy that occurs in children, usually between the ages of 3 months and 18 months. The seizures manifest typically as clusters of either flexor or extensor epileptic spasms, which are often coincident with an arrest or regression of neurodevelopment. The electroencephalograph characteristically, but not always, shows a chaotic high voltage interictal pattern known as hypsarrhythmia. Many underlying aetiologies, such as tuberous sclerosis complex, trisomy 21, neuronal migration disorders, and hypoxic-ischaemic encephalopathy, have been associated with infantile spasms but in a significant minority of cases no cause is found. There has been much debate about the most effective treatment modality for these patients but there appears to be a relatively wide consensus that the two most effective therapies are either the GABA-ergic anticonvulsant, vigabatrin, or hormonal therapies (prednisolone, adrenocorticotrophin hormone [ACTH], or synthetic ACTH). 1It has been known since the 1980s that vigabatrin usage in animals was associated with the development of intramyelinic oedema in the central nervous system, most notably in the cerebellum, reticular formation and optic tracts in rats, and columns of the fornix and the optic tracts in dogs. 2,3 Recently reports have surfaced in the literature linking vigabatrin usage in humans with characteristic magnetic resonance imaging (MRI) changes in the globus pallidus, thalamus, brain stem, and dentate nuclei of the cerebellum. 4,5 These changes appear to be dose-dependent

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