Gatekeeper Improves Voluntary Contractility in Patients With Fecal Incontinence

Background. Gatekeeper (GK) has shown to be safe and effective in patients with fecal incontinence (FI). We aimed to understand its mechanism of action by comparing pre- and post-implant change in the external anal sphincter (EAS) contractility. Methods. Study of EAS contractility was conducted in 16 FI females (median age = 69 years) before and after implant of 6 GK prostheses. Muscle tension (Tm), expressed in millinewtons per centimeter squared, mN(cm2) 121, was calculated using the equation Tm = P(ri)(tm) 121, where P is the average maximum squeeze pressure and ri and tm the inner radius and thickness of the EAS, respectively. The effect of a predefined set of covariates on Tm was tested by restricted maximum likelihood models. Results. Compared with baseline, despite unchanged tm (2.7 [2.5-2.8] vs 2.5 [2.2-2.8] mm; P =.31 mm), a significant increase in P (median = 45.8 [26.5-75.8] vs 60.4 [43.1-88.1] mm Hg; P =.017), and ri (12.4 [11.5-13.4] vs 18.7 [17.3-19.6] mm; P <.001) resulted in an increase in Tm (233.2 [123.8-303.2] vs 490.8 [286.9-562.4] mN(cm2) 121; P <.001) at 12 months after GK implant. Twelve-month follow-up improvements were also observed on Cleveland Clinic FI score (8-point median decrease; P =.0001), St Marks FI score (10-point median decrease; P <.0001), and American Medical Systems score (39-point median decrease; P <.0001). Restricted maximum likelihood models showed that years of onset of FI was negatively associated with change in Tm (P =.048). Conclusions. GK-related EAS compression positively influences muscle contractility by increasing ri, with consequent increase in Tm (length-tension relationship). Further studies are needed to confirm the long-term effectiveness of GK

Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: A case–control matched analysis from a large multicenter study

Background: Improved outcome in tobacco smoking patients with non-small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first-line immunotherapy in patients with high PD-L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. Methods: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first-line pembrolizumab and platinum-based chemotherapy. Results: A total of 962 NSCLC patients with PD-L1 expression ≥50% who received first-line pembrolizumab and 462 NSCLC patients who received first-line platinum-based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression-free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. Conclusions: Among metastatic NSCLC patients with PD-L1 expression ≥50% receiving first-line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first-line chemotherapy

Prospective evaluation of a new device for the treatment of anal fistulas

AIM: To evaluate the safety of the implantation of a new device for the treatment of anal fistulas. The short-term clinical efficacy was also assessed. METHODS: This study took place at a tertiary care university hospital. Patients with a complex anal fistula of cryptoglandular origin were enrolled in the study and were treated with insertion of the new device. All patients were evaluated by clinical and physical examination, including an endoanal ultrasound at the baseline, and then at the 2 wk and 1, 2, 3 and 6-mo follow-up visits. RESULTS: Morbidity, continence status, and success rate were the main outcome measures. Ten patients underwent the placement of the new device. The fistulas were transphincteric in eight patients and extrasphincteric in the remaining two. The median duration of the surgical procedure was 34.5 (range, 27-42) min. Neither intra- nor postoperative complications occurred, and all patients were discharged the day after the procedure. At the 6-mo follow-up evaluation, the final success rate was 70%. Three failures were registered: a device expulsion (on the 10th postoperative day), the persistence of inflammatory tissue around the fistula tract (at the 2-mo follow up), and the persistence of serum discharge (at the 6-mo follow up). No patient experienced any change incontinence, as assessed by the Cleveland Clinic Fecal Incontinence score. CONCLUSION: The technical procedure is simple and has low risk of perioperative morbidity. The pre- and post-operative continence status did not change in any of the patients. The initial results at the 6-mo follow up seem to be promising. However, a longer follow-up period and a larger sample size are needed to confirm these preliminary results

Transanal hemorrhoidal dearterialization (THD) for hemorrhoidal disease: a single-center study on 1000 consecutive cases and a review of the literature

Background: The transanal hemorrhoidal dearterialization (THD) Doppler procedure is a minimally invasive technique to treat symptomatic hemorrhoids. The aim of the study was to assess the clinical efficacy and the satisfaction of patients in a large series treated with THD and to review the relevant literature. Methods: In this retrospective, single-institution, study consecutive patients with grade 2, 3, or 4 hemorrhoidal disease were treated with the THD Doppler procedure. Dearterialization was performed in all cases and mucopexy in case of prolapse. The dearterialization procedure evolved from \u201cproximal artery ligation\u201d to \u201cdistal Doppler-guided dearterialization.\u201d Follow-up was scheduled at 15\ua0days, 1, 3, 12\ua0months, and once a year thereafter. Complications were recorded. Clinical efficacy was assessed comparing both frequency of symptoms and disease grading (Goligher\u2019s classification) at baseline versus last follow-up. Uni-/multivariate analysis evaluated factors affecting the outcome. Results: There were 1000 patients (619 men; mean age: 48.6\ua0years, range 19\u201388\ua0years). Acute postoperative bleeding was observed in 14 patients (1.4%), pain/tenesmus in 31 patients (3.1%), and urinary retention in 23 patients (2.3%). At mean follow-up duration of 44\ua0\ub1\ua029\ua0months, the symptomatic recurrence rate was 9.5% (95 patients; bleeding in 12 (1.2%), prolapse in 46 (4.6%), and bleeding and prolapse in 37 (3.7%) patients). The recurrence rate was 8.5, 8.7, and 18.1% in patients with grade 2, 3, and 4 hemorrhoids, respectively. Seventy out of 95 patients with recurrence needed surgery (reoperation rate: 7.0%). At final follow-up and taking into account the reoperations, 95.7% of patients had no hemorrhoidal disease on examination. Younger age, grade 4 disease, and high artery ligation affected the outcome negatively. Conclusions: Our results show that the THD Doppler procedure is safe and effective in patients with hemorrhoidal disease and associated with low morbidity and recurrence rates and a high rate percentage of treatment success

Multicentre observational study of the Gatekeeper\u2122 for faecal incontinence

A variety of therapeutic approaches are available for faecal incontinence. Implantation of Gatekeeper\u2122 prostheses is a new promising option. The primary endpoint of this prospective observational multicentre study was to assess the clinical efficacy of Gatekeeper\u2122 implantation in patients with faecal incontinence. Secondary endpoints included the assessment of patients' quality of life, and the feasibility and safety of implantation

Gatekeeper Improves Voluntary Contractility in Patients With Fecal Incontinence

Abstract Background. Gatekeeper (GK) has shown to be safe and effective in patients with fecal incontinence (FI). We aimed to understand its mechanism of action by comparing pre- and post-implant change in the external anal sphincter (EAS) contractility. Methods. Study of EAS contractility was conducted in 16 FI females (median age = 69 years) before and after implant of 6 GK prostheses. Muscle tension (Tm), expressed in millinewtons per centimeter squared, mN(cm2 ) −1, was calculated using the equation Tm = P(ri )(tm)−1, where P is the average maximum squeeze pressure and r i and tm the inner radius and thickness of the EAS, respectively. The effect of a predefined set of covariates on Tm was tested by restricted maximum likelihood models. Results. Compared with baseline, despite unchanged tm (2.7 [2.5-2.8] vs 2.5 [2.2-2.8] mm; P = .31 mm), a significant increase in P (median = 45.8 [26.5-75.8] vs 60.4 [43.1-88.1] mm Hg; P = .017), and r i (12.4 [11.5-13.4] vs 18.7 [17.3-19.6] mm; P < .001) resulted in an increase in Tm (233.2 [123.8-303.2] vs 490.8 [286.9-562.4] mN(cm2 ) −1; P < .001) at 12 months after GK implant. Twelve-month follow-up improvements were also observed on Cleveland Clinic FI score (8-point median decrease; P = .0001), St Marks FI score (10-point median decrease; P < .0001), and American Medical Systems score (39-point median decrease; P < .0001). Restricted maximum likelihood models showed that years of onset of FI was negatively associated with change in Tm (P = .048). Conclusions. GK-related EAS compression positively influences muscle contractility by increasing r i , with consequent increase in Tm (length-tension relationship). Further studies are needed to confirm the long-term effectiveness of GK

Immunopathological characterization of cryptoglandular anal fistula: a pilot study investigating its pathogenesis

Aim: The pathogenesis of cryptoglandular anal fistula (AF) is still under debate. Tissue inflammation could play a primary role. The pathological process of epithelial mesenchymal transition (EMT) might be involved but has never been investigated. Method: In a prospective pilot study, 12 patients with an AF had a fistulectomy. The excised track was divided into proximal (intrasphincteric) and distal (extrasphincteric) parts which were subjected to standard histopathological examination. The cytokines IL-8 and IL-1beta were analysed as markers of inflammation, while EMT was evaluated by expression of TGF-beta, Vimentin, Zeb-1, Snail and E-cadherin. The mRNA and protein expression of these molecules was investigated by real-time PCR (RT-PCR), Western blot analysis and immunohistochemistry and was compared with that of the normal adjacent tissue. Results: Chronic inflammation and granulation tissue and a stratified epithelium were evident on standard histopathological examination. The cytokine IL-8 was more expressed in the proximal than the distal part of the track (fold increase 4.34 vs 3.60), while the reverse was found for IL-1beta (fold increase 1.33 vs 2.01); both were more intensely expressed compared with the normal anal mucosa. EMT was demonstrated, in both proximal and distal parts of the track, with an increase of TGF-beta, Vimentin, Zeb-1 and Snail and a mean decrease of E-cadherin. Western blot analysis and immunohistochemistry confirmed the protein expression. Conclusion: The study suggests that chronic inflammation is present in cryptoglandular fistulas. The inflammatory pattern might be different in the proximal than in the distal part of the fistula track. The cytokines IL-1beta and IL-8 could play a possible role in fistula formation. The study demonstrates for the first time the potential importance of EMT in the pathogenesis of cryptoglandular AF