A129 THE VALUE OF REPEAT MANOMETRIC TESTING

Background While motility disorders may evolve over time, there is scant guidance around the role of repeat high-resolution esophageal manometry (HRM). Given the invasive nature of HRM and the implications on financial cost and patient discomfort, it is obvious that the emphasis should be on minimizing unnecessary repeat examinations. However, there are no recommendations around indications or timing of repeat HRM. Aims We aimed to determine the outcomes in patients who underwent repeat manometry and look for predictors of progression to achalasia or major motility disorder. Methods Consecutive reports from HRM studies performed between Aug 2013 – May 2017 were retrospectively analyzed. All patients with ≥ 2 HRM studies were included. Studies without a Chicago classification diagnosis were excluded. Chi-squared analysis was performed to determine if initial HRM diagnosis was associated with change in diagnosis on follow-up HRM. Initial and follow-up manometric parameters were compared with paired T-tests. Binary logistic regression analysis was performed to look for predictors of progression to achalasia or major motility disorder. Results 134 patients underwent ≥ 2 HRM studies. Initial diagnoses were IEM (45 patients [33.6%], EGJOO (34 [25.4%], absent peristalsis (18 [13.4%], achalasia (11 [8.2%], DES (4 [3.0%]), and JH (3 [2.2%]; 29 (14.2%) of patients had a normal HRM. 109 (81.3%) patients underwent 2 HRM, 18 (13.4%) 3 HRM, 4 (3%) 4 HRM, and 3 (2.2%) 5 HRM. The final follow-up HRM occurred after a median 496 [80 – 1823] days. 72 (53.7%) of patients had no change from their initial diagnosis. Patients with an initial diagnosis of DES were significantly more likely to have a change in diagnosis on the final follow-up (3 normal:1 IEM) (p = .043). No other classes reached significance. Patients with IEM had a significantly higher mean DCI (395.1 [0 - 3248] vs 790.8 [0 – 10715.0], p = .006) and IRP (4.5 [-10.4 – 14.2] vs [6.6 [-6.2 – 21.0], p = .017) on their follow-up HRM. 4 patients without achalasia (3 EGJOO:1 IEM) on their index HRM had a diagnosis of achalasia on their final HRM. The median IRP in non-achalasia patients with a diagnosis of achalasia on final HRM (22.3 [8.4 – 30.7] was significantly higher than those without a diagnosis of achalasia on final HRM (6.6 [-10.4 – 39.8]) (p = .013); however no manometric criteria or initial HRM diagnoses predicted progression to achalasia or major motility disorder on binary logistic regression analysis. Conclusions In most patients, repeat manometry did not change the manometric diagnosis. Patients with DES were significantly likely to have their diagnosis change with repeat HRM, and most of these patients had normalization of their HRM. Manometric parameters in IEM appear to improve over time. This finding could reflect interval therapy, or shed some light on the natural history of this disease. Funding Agencies None

Ten years of follow-up in a large family with familial hemiplegic migraine type 1: Clinical course and implications for treatment

Background Familial hemiplegic migraine (FHM) is a rare, genetic form of migraine with aura. The severity of the aura imposes an effective prophylaxis that is currently based on standard anti-migraine drugs. To this concern, only short-term reports are currently available. Methods Eight patients from a multigenerational FHM type 1 family harbouring a T666M mutation in the CACNA1A gene were referred to our ataxia outpatient clinic. Medical history, general and neurological examination as well as therapeutic approaches were recorded regularly on a routine basis for an average period of 13 years (range 9–15 years). Brain imaging studies and EEG data were also collected. Results Our long-term follow-up revealed that ictal manifestations, which usually improve after the adolescence, may reoccur later in the adulthood. Permanent neurological signs as assessed by means of clinical evaluation as well as follow-up MRIs, EEGs and neuropsychological testing remained stable. Interval therapy with non-selective calcium antagonists reduced the burden of migraine attacks and was well tolerated in the long term.

In VitroEmergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

ABSTRACTHealth care-associated infections present a major threat to modern medical care. Six worrisome nosocomial pathogens—Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspp.—are collectively referred to as the “ESKAPE bugs.” They are notorious for extensive multidrug resistance, yet persistence, or the phenotypic tolerance displayed by a variant subpopulation, remains underappreciated in these pathogens. Importantly, persistence can prevent eradication of antibiotic-sensitive bacterial populations and is thought to act as a catalyst for the development of genetic resistance. Concentration- and time-dependent aminoglycoside killing experiments were used to investigate persistence in the ESKAPE pathogens. Additionally, a recently developed method for the experimental evolution of persistence was employed to investigate adaptation to high-dose, extended-interval aminoglycoside therapyin vitro. We show that ESKAPE pathogens exhibit biphasic killing kinetics, indicative of persister formation.In vitrocycling between aminoglycoside killing and persister cell regrowth, evocative of clinical high-dose extended-interval therapy, caused a 37- to 213-fold increase in persistence without the emergence of resistance. Increased persistence also manifested in biofilms and provided cross-tolerance to different clinically important antibiotics. Together, our results highlight a possible drawback of intermittent, high-dose antibiotic therapy and suggest that clinical diagnostics might benefit from taking into account persistence.

Thrombin Generation Test During Asparaginase Treatment In Children With Acute Lymphoblastic Leukemia

Asparaginase (Aase) and corticosteroid (CS) used to treat acute lymphoblastic leukemia (ALL) in children during the Induction and Late Intensification phases have adverse effects on coagulation and increase the incidence of thrombotic events. Aase and CS reduce both pro- and antithrombotic factors and most studies have evaluated the individual components of the coagulation system to infer the prothrombotic profile. However, global haemostatic potential of these children and its changes during treatment are poorly reported. We aimed to characterize the global haemostatic phenotype of ALL patients during native Aase therapy, using a global haemostatic assay, the Calibrated Automated Thrombogram® (CAT) method of thrombin generation (TG) in B lineage ALL children treated according to the latest CLG-EORTC first-line protocol (a BFM derived protocol). CAT method was performed on platelets-poor plasma (PPP) at diagnosis (day 1), before each Aase infusion (8 during Induction and 4 during Late Intensification), and at distance of Aase infusion (during and after Interval Therapy and at start of Maintenance). TG was triggered using 1pM tissue factor (TF) and 4µM phospholipids (PL), with and without addition of thrombomodulin (TM). Endogenous Thrombin Potential (ETP) and Peak were monitored and the interquartile range was compared to the [2,5 – 97,5] percentile range of normal controls (NC) of the same range of age (n=28). Protein C activity (PC), free Protein S (PS), antithrombin (AT) and fibrinogen levels were also measured. Results Thirty six children were included (20 boys and 16 girls). Their median age at diagnosis was 3.7 years (range 1-14). Twenty had pre-B ALL and 16 common ALL. Elevated ETP and Peak of TG in ALL patients above the 97,5 percentile of NC were noted at diagnosis and persisted during all the Induction phase. During Interval Therapy and later at start of Maintenance, ETP and Peak returned to values below 97.5 percentile of NC. During Late Intensification, ETP and Peak levels increased above the 97.5 percentile of NC. At all time points studied the variation of ETP and Peak levels were similar in the presence and absence of TM. PC, PS, AT and fibrinogen levels decreased during Induction phase with median PS level remaining within the 2.5-97.5 percentile of NC and median AT and PC levels reaching a value lower than the 2.5 percentile of NC at the time of the 7th and 8th Aase infusion respectively (day 32 and 35). Fibrinogen levels were below the 2.5 percentile of NC during Induction from day 15 to day 29. Among the 36 analyzed patients, 2 experienced 3 symptomatic thromboses. One sub-clavian thrombosis occurred during Induction on day 22 and 1 jugular vein thrombosis occurred in a second child after completion of Induction on day 50 (13 days after the 8thAase infusion). These 2 events were concurrent with a central venous catheter infection. The second patient also developed during Late Intensification a cerebral thrombosis in the longitudinal sinus. Concomitant to these three events, ETP and Peak values of these patients were above the P75 value of ALL patients sampled at the same time points compatible with a marked prothrombotic profile and a higher risk of thrombosis. This study suggests that TG is a promising global assay to evaluate the hypercoagulable state in ALL children under treatment. TG reveals an increased thrombin potential which is present early at diagnosis, persists during Induction and reappears during Late Intensification. This observation is consistent with the high incidence of thrombotic events previously described during Induction and until 10 days after the last Aase infusion. TG profiles observed in patients who experienced thrombotic events suggest that this assay could be used as a predictive tool since their TG parameters were above P75 value of the ALL children tested. Further investigations are needed to address this issue. Disclosures: No relevant conflicts of interest to declare.