Endoscopic dilatation improves long-term dysphagia following head and neck cancer therapies: a randomized control trial.

Long-term pharyngeal dysphagia is a common complication following head and neck cancer (HNC) therapies. High-level evidence for pharyngoesophageal junction (POJ) dilatation as a treatment in this population is lacking. We aimed to evaluate the safety and efficacy of POJ dilatation in dysphagic HNC survivors. This single-center, single-blind, placebo-controlled trial (St George Hospital, Sydney, Australia) randomly assigned (1:1) HNC survivors with long-term dysphagia (≥12 months postcompleted HNC therapies) to receive either graded endoscopic dilatations or sham dilatation (placebo). Patients were blinded to intervention types. Two strata were used for permuted randomization: (1) HNC therapies (total laryngectomy vs. chemoradiation alone); (2) Prior POJ dilatation (nil vs. previous dilatation). The primary endpoint was a short-term clinical response in swallowing function (3 months), defined as (1) a decrease in Sydney Swallow Questionnaire score by ≥200 or a score ≤ ULN; and (2) satisfactory global clinical assessment. The secondary endpoints were dysphagia relapse and serious adverse events. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000707369). Between 13 January 2013 and 16 January 2017, 41 patients were randomly assigned to endoscopic dilatation (n = 21) or placebo (n = 20). The short-term response rate in the endoscopic dilatation group was 76% (n = 16), compared with 5% (n = 1) in the placebo group (P < 0.001). There were no serious adverse events. The finding of a mucosal tear postdilatation was associated strongly with clinical response (OR 13.4, 95% CI [2.4, 74.9], P = 0.003). Kaplan-Meier estimate of dysphagia relapse is 50% by 9.6 months (95% CI [6.0, 19.2]) from completion of dilatation. Endoscopic dilatation of the POJ is a safe and efficacious therapy for the treatment of long-term dysphagia in HNC survivors. Close follow-up and repeat dilatation are necessary given the high dysphagia relapse rate.

The critical importance of pharyngeal contractile forces on the validity of intrabolus pressure as a predictor of impaired pharyngo-esophageal junction compliance.

INTRODUCTION: Restrictive defects of the pharyngo-esophageal junction (PEJ) are common in both structural and neurological disorders and are amenable to therapies aiming to reduce outflow resistance. Intrabolus pressure (IBP) acquired with high-resolution manometry and impedance (HRMI) is an indicator of resistance and a marker of reduced PEJ compliance. Constraints and limitations of IBP as well as the optimal IBP parameter remain undefined. AIMS: To determine: (i) the impact of peak pharyngeal pressure (PeakP) on the diagnostic accuracy of IBP for the detection of a restrictive defect at the PEJ and (ii) the optimal IBP parameter for this purpose. METHODS: In 52 dysphagic patients previously treated for head and neck cancer. Five candidate IBP measures and PeakP were obtained with HRMI, as well as a presence of a stricture determined by a mucosal tear after endoscopic dilatation. Predictive values of IBP measures were evaluated by receiver operating characteristic (ROC) analysis for all patients and reiterated as patients with lowest PeakP were progressively removed from the cohort. RESULTS: All IBP parameters had fair to good accuracy at predicting strictures. Intrabolus pressure measured at a discrete point of maximum admittance 1 cm above the maximal excursion of the upper esophageal sphincter had highest sensitivity (0.76) and specificity (0.78). When PeakP was at least 57 mm Hg both sensitivity and specificity improved to 0.9. CONCLUSIONS: Pharyngeal propulsive force has substantial impact on the accuracy of IBP as a predictor of a PEJ stricture. When PeakP is ≥57 mm Hg, an elevated IBP is highly predictive of a restrictive defect at the PEJ.

Novel Intra-Procedural Distensibility Measurement Accurately Predicts Immediate Outcome of Pneumatic Dilatation for Idiopathic Achalasia.

OBJECTIVES: Often 2-3 graduated pneumatic dilatations (PD) are required to treat achalasia as there is no current intra-procedural predictor of clinical response. Distensibility measurements using functional lumen imaging probe (FLIP) may provide an intra-procedural predictor of outcome. Our aim was to determine the optimal criterion for esophagogastric junction (EGJ) distensibility measurements during PD that predicts immediate clinical response. METHODS: EGJ distensibility was prospectively measured using FLIP immediately pre- and post-PD. The EGJ distensibility index (EGJ-DI) was defined as a ratio of the narrowest cross-sectional area and the corresponding intra-bag pressure at 40 ml distension. Immediate and short-term clinical responses were defined as Eckardt score ≤3 assessed 2 weeks Post-PD and at 3-month follow-up, respectively. RESULTS: In 54 patients, we performed thirty-seven 30 mm; twenty 35 mm and six 40 mm PDs. The short-term response rate to the graded PD was 93% (27/29) in newly diagnosed achalasia; 87% (13/15) and 70% (7/10) in those who had relapsed after previous PD and Heller's Myotomy, respectively. Among those demonstrating an immediate response, EGJ-DI increased by an average of 4.5 mm2/mmHg (95% CI (3.5, 5.5) (P<0.001). Within-subject Δ EGJ-DI was highly predictive of immediate clinical response with AUROC of 0.89 (95% CI [0.80, 0.98], P<0.001). An increment in EGJ-DI of 1.8 mm2/mmHg after a single PD predicts an immediate response with an accuracy of 87%. CONCLUSIONS: FLIP-measured Δ EGJ-DI is a novel intra-procedural tool that accurately predicts immediate clinical response to PD in achalasia. This technique may potentially dictate an immediate mechanism to "step-up" dilator size within a single endoscopy session.

Long-term outcome following pneumatic dilatation as initial therapy for idiopathic achalasia: an 18-year single-centre experience.

BACKGROUND: Relapse after treatment for idiopathic achalasia is common and long-term outcome data are limited. AIM: To determine the cumulative relapse rate and long-term outcome after pneumatic dilatation (PD) for achalasia in a tertiary referral centre. METHODS: A retrospective study of 301 patients with achalasia treated with PD as first-line therapy. Short-term outcome was measured at 12 months. Long-term outcome was assessed in those who were in remission at 12 months by cumulative relapse rate and cross-sectional analysis of long-term remission rate regardless of any interval therapy, using a validated achalasia-specific questionnaire. RESULTS: Eighty-two percent of patients were in remission 12 months following initial PD. Relapse rates thereafter were 18% by 2 years; 41% by 5 years and 60% by 10 years. Whilst 43% patients underwent additional treatments [PD (29%), myotomy (11%) or botulinum toxin (3%)] beyond 12 months, 32% of those who had not received interval therapy had relapsed at cross-sectional analysis. After a mean follow-up of 9.3 years, regardless of nature, timing or frequency of any interval therapy, 71% (79/111) patients were in remission. The perforation rate from PD was 2%. Chest pain had a poor predictive value (24%) for perforation. CONCLUSIONS: Long-term relapse is common following pneumatic dilatation. While on-demand pneumatic dilatation for relapse yields a good response, one-third of relapsers neither seek medical attention nor receive interval therapy. Close follow-up with timely repeat dilatation is necessary for a good long-term outcome. Given the poor predictive value of chest pain for perforation, routine gastrografin swallow is recommended postdilatation.

Identification of a lexA gene in, and construction of a lexA mutant of, Xanthomonas campestris pv. citri.

The lexA gene of Xanthomonas campestris pathovar citri (X.c. pv. citri) was cloned and sequenced. The 639-bp open reading frame encodes a protein of 213 amino acids that shares substantial sequence homology with the products of previously characterized lexA genes, sharing 46% identity with the LexA protein of Escherichia coli. Amino acids required for autocatalytic cleavage of LexA are conserved in the X.c. pv. citri protein, whereas domains thought to mediate DNA binding differ markedly from those of LexA proteins from E. coli and other bacteria. The X.c. pv. citri LexA protein was overexpressed in E. coli, and SDS-polyacrylamide gel electrophoresis revealed a molecular size of 23 kDa for the purified protein. A lexA mutant of X.c. pv. citri was constructed by gene replacement, and the basal level of recA expression in this mutant was shown to be similar to that for wild-type cells exposed to a DNA-damaging agent. These results indicate that LexA functions as a repressor of recA expression in X.c. pv. citri.

Identification of the promoter region of the Xanthomonas campestris pv. citri recA gene responsible for induction by DNA-damaging agents.

The abundance of the RecA protein and of recA transcripts was markedly increased on exposure of Xanthomonas campestris pathovar citri to various DNA-damaging agents, including mitomycin C. The promoter sequence responsible for mediating the sensitivity of recA expression to DNA damage was investigated by subcloning a 426-bp restriction fragment of the 5' untranslated and coding region of the gene into a promoterless vector containing the luxAB genes of Vibrio fischeri. Xanthomonas campestris pv. citri cells transformed with this vector responded to DNA-damaging agents with a marked increase in luciferase activity. Deletion of nucleotides from the 5' end of the recA fragment inserted into the reporter plasmid revealed that the 58 bp upstream of the transcription initiation site are sufficient to mediate induction of recA expression by mitomycin C.