Hereditary angioedema (HAE) is a rare autosomal dominant disease due to C1 esterase inhibitor deficiency (C1-INH). The disease is characterized by subcutaneous and submucosal edema in the absence of urticaria due to the accumulation of bradykinin. This descriptive study aimed to evaluate the clinical characteristics of patients with a confirmed diagnosis of HAE referred to our Outpatient Clinic between December 2009 and November 2017. Fifty-one patients (38 F, 13 M) with a mean age of 32 years (range: 7–70 y) were included. Family history of HAE was reported in 70% (36/51) of the cases; 33/46 patients became symptomatic by 18 years of age. The median time between onset of symptoms and diagnosis was 13 years (3 mo–50 y). The most frequent triggering factors for attacks were stress (74.4%), trauma (56.4%), and hormonal variations (56%). The main symptoms were subcutaneous edema in 93.5% (43/46) of patients, gastrointestinal symptoms in 84.8% (39/46), and obstruction in the upper airways in 34.8% (16/46). Hospitalization occurred in 65.2%, of whom 13.3% had to be transferred to the Intensive Care Unit. Prophylactic treatment was instituted in 87% (40/46) of patients, and 56.5% (26/46) required additional treatment to control attacks. Owing to our data collection over a period of 8 years, a significant number of patients were identified by this HAE reference center. Despite early recognition and prophylactic treatment, a high percentage of patients were hospitalized. HAE is still diagnosed late, reinforcing the need for more reference centers specialized in diagnosis and educational projects for health professionals.

455 Background: The POUT trial (CRUK/11/027; NCT01993979) previously reported (with median follow-up 30.3 months) that adjuvant chemotherapy improves disease free survival (DFS) for patients (pts) with histologically confirmed pT2-T4 N0-3 M0 UTUC. Here we present results of a pre-planned analysis updating the primary endpoint and reporting key secondary endpoints including overall survival. Methods: 261 pts with UTUC were enrolled following nephro-ureterectomy and randomised (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly imaging and cystoscopy for 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. Primary endpoint was DFS. Secondary endpoints included metastasis free survival (MFS), overall survival (OS), toxicity and patient reported quality of life (QoL). The trial closed to recruitment early on advice of the independent data monitoring committee due to evidence of efficacy. Time-to-event endpoints are analysed (intention-to-treat) by Cox proportional hazard models. Unadjusted and adjusted (by nodal status, planned chemotherapy type, microscopic margin status, pathological stage) hazard ratios (HR, < 1 favouring chemotherapy) are reported. Results: From May 2012 to Nov 2017, 261 pts were recruited (129 surveillance; 132 chemotherapy) at 56 UK centres. One participant withdrew consent for data usage and was excluded from analyses. Pts had median age 69 years (range 37-88), 28% pT2, 66% pT3; 91% pN0. To 09/09/2020, median follow up was 48.1 months (IQR: 36.0-60.1). The unadjusted/adjusted HR for DFS was 0.48 (95% CI: 0.33-0.71; p = 0.0003) / 0.50 (95%CI: 0.34-0.75; p = 0.001), and for MFS was 0.52 (95% CI: 0.35-0.77; p = 0.001) / 0.54 (95% CI: 0.36-0.81; p = 0.002). 93/260 (35.8%) pts have died (52/129 [40.3%] surveillance and 41/131 [31.3%] chemotherapy). Chemotherapy conferred a non-statistically significant 28% reduction in relative risk of death (HR = 0.72, 95% CI: 0.47-1.08; p = 0.11; adjusted HR = 0.79, 95% CI: 0.52-1.19; p = 0.26). 3 year OS was surveillance: 67% (95% CI: 58-74%; chemotherapy: 79% (71%-85%). There was no evidence of long-term toxicity associated with chemotherapy (Wilcoxon rank-sum test p-value for worst grade post-6 months = 0.32). Most common grade 2+ adverse events were hypertension (25/240 [10.4%]), lethargy (25/240 [10.4%]) and hearing loss (13/240 [5.4%]). There was no evidence of statistically or clinically relevant differences in QoL. 12 months after treatment (EORTC Q30 global health status mean difference 4.1 and 4.8 at 12 and 24 months respectively in favour of chemotherapy). Conclusions: With additional follow-up, the previously reported DFS benefit for chemotherapy was maintained with no detrimental long-term toxicity. No statistically significant improvement in OS was observed. Clinical trial information: NCT01993979.

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Introduction: Variations in the POLG gene are the most common causes of mitochondrial disease of autosomal inheritance, and may be present in about 2% of the population. Case report: Case 1. CMAM, male, 48-year-old, complaining of bilateral eyelid ptosis with onset in adolescence. Since the age of six, he has been diagnosed with epilepsy. After five years of follow-up, he developed sensory ataxia. After 10 years he began to present dysarthria, dysphagia, tremor and pyramidal syndrome. Case 2. ASB, female, 42 years old, at 20 years old presented generalized clonic tonic crisis during the second and third trimesters of pregnancy; at 35 years of age she complained of tingling in plants and legs; at 37 years she noticed bilateral eyelid ptosis and at 39 years she noticed the presence of slurred speech and fatigue on small efforts. He has 3 siblings with similar symptoms and great difficulty walking. No history of consanguinity. Propedeutics: Normal serum lactate and CPK dosage; muscle biopsy showed variation in the caliber of muscle fibers, with the presence of “ragged red fibers” in Gomori’s Trichrome stain. Cranial magnetic resonance imaging: mild cerebellar atrophy in patient 1 and normal in patient 2. Electroneuromyography reveled absence of sensory action potentials in all nerves studied in both cases. New generation sequencing myopathy panel revealed pathogenic variant in homozygosis in the POLG c.1399G>A gene (p.Ala467Thr). Results: The patients received the diagnosis of mitochondrial disease, presenting complex clinical phenotype. Conclusion: DNA polymerase gamma is the enzyme responsible for replicating and maintaining mitochondrial DNA, encoded by nuclear DNA. The c.1399G>A variant in exon7 causes a replacement of an alanine with threonine (A467T), and is one of the causes of ataxia, such as spinocerebellar ataxia with epilepsy; autosomal recessive mitochondrial ataxia, sensory neuropathy, dysarthria and ophthalmoparesis and myoclonic epilepsy, myopathy and sensory ataxia. However, most of the time, they present a continuum between the phenotypes described.

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