Introduction

Local injection of darvadstrocel, a suspension of expanded adipose-derived allogenic mesenchymal stem cells with anti-inflammatory and immunomodulatory properties, represents a novel effective treatment for complex perianal fistulas in patients with Crohn's disease (CD).

Aims & Methods

The aim of this systematic review was to summarize reported evidence on the real-world outcomes of darvadstrocel for complex perianal fistulas in CD and to conduct a meta-analysis of effectiveness and safety data. A comprehensive search was led in electronic databases PubMed, Web of Science, EMBASE, Scopus and ScienceDirect until 15 April 2024 to identify observational studies evaluating darvadstrocel for complex fistulizing CD. Joanna Briggs Institute (JBI) Critical Appraisal tool was used to assess the study quality and the risk of bias. Random-effects meta-analysis model was used to calculate the pooled rates of clinical and safety outcomes. Heterogeneity across studies was assessed with the I² statistic according to Cochrane Handbook. The primary endpoint was clinical remission (closure of all treated external openings) at months 6 and 12. Adverse events (AE) were reported as incidence rates (IRs) per 100 patients-year (PY) of exposure.

Results

Of the 72 citations identified, 12 studies with 595 patients were eligible for inclusion. According to JBI criteria, 7 and 5 studies showed a low or moderate risk of bias, respectively. The pooled rate of patients achieving clinical remission was 68.1% at month 6 (95% CI 63.4-72.7) and 77.2% (95% CI 70.1-83.8) at month 12 (Table). Median time to achieve fistula closure was 6 weeks (95% CI 3.8-9.5). Combined remission defined as clinical remission and absence of collections > 2 cm confirmed by magnetic resonance imaging was reported in 60.6% and in 69.7% of patients at month 6 and month 12, respectively. Clinical response was observed in 79.9% and in 81.7% of patients at month 6 and month 12, respectively. The rate of patients with treatment failure, defined as no clinical remission, at last follow-up (mean 18.7 month; SD 9.9) was 34.5% (95% CI 25.7-43.9). Linear regression analysis indicated that failure rate was independent of follow-up time (R² = 0.001). For all effectiveness outcomes, between-study heterogeneity might not be important (Table).
Pooled IR per 100 PY of AEs and serious AEs were 19.6 and 3.2, respectively. IR per 100 PY of new perianal abscesses and reoperations were 16.9 and 7.1, respectively. For safety analyses, between-study heterogeneity ranged between moderate and substantial (Table).

Conclusion

Real-world evidence supports the efficacy and safety of darvadstrocel for complex perianal fistulas in CD. Studies reported high fistula healing rates that can be sustained long-term in most patients, with high homogeneity across studies. Darvadstrocel showed a favourable safety profile.

References

1. Panés J, García-Olmo D, Van Assche G, et al; ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388:1281-1290.
2. Panés J, García-Olmo D, Van Assche G, et al. Long-term efficacy and safety of stem cell therapy [Cx601] for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018;154:1334–42.e4.

Disclosure

CT has served as a speaker, consultant, and advisory board member for MSD, AbbVie, Pfizer, Takeda, Galapagos, Lilly, Fresenius Kabi, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, and Tillots. MAG, DO, ONL, RZ and CA have no conflicts of interest to declare.

Introduction

As no direct comparison between IBD drugs to prevent endoscopic postoperative recurrence (POR) in Crohn’s disease (CD) are available, hierarchizing these therapeutic options remains challenging.

Aims & Methods

The objective of this network meta-analysis was to compare the effectiveness of treatments to prevent endoscopic POR of CD.
We performed a systematic review and network meta-analysis of comparative studies conducted in adults, evaluating a treatment to prevent endoscopic POR after ileocecal resection. The selection of studies was made according to PRISMA guidelines. The primary endpoint was endoscopic POR at 6 months defined as Rutgeerts score ≥ i2.
The network meta-analysis was carried out according to a random effects model. The results are presented as odds ratio (OR) with 95% confidence interval, adjusted for risk factors of POR. The risk of bias of the studies was assessed according to the Cochrane risk-of-bias tool for randomized trials and overall statistical heterogeneity between studies was assessed using τ.
The SUCRA ranking method (surface under the cumulative ranking) was used to rank the treatments.

Results

Twenty studies were included in this network meta-analysis, including a total of 2414 patients. Overall heterogeneity was moderate (τ =0.34). After adjustment for POR risk factors, ustekinumab (OR = 0.23 [0.07-0.70]), vedolizumab (OR = 0.17 [0.05 -0.59]), infliximab (OR = (0.18 [0.36-0.88]) and adalimumab (OR = 0.17 [0.07-0.42]) were superior to placebo to prevent endoscopic POR, contrary to 5-ASA (OR = 0.79 [0.42 -1.48]) and thiopurines (RR = 0.52 [0.22-1.24]) (Table 1). Ustekinumab (OR = 0.29 [0.08-0.99]), vedolizumab (OR = 0.22 [0.06-0.85]), infliximab (OR = (0.23 [0.09-0.54]) and adalimumab (OR = 0.22 [0.08-0.59]) were more effective than 5-ASA in preventing endoscopic POR. Adalimumab (OR = 0.33 [0.15-0.74]) and infliximab (OR = 0.34 [0.13-0.87]) were also more effective than thiopurines.
We observed no difference in efficacy between the 4 biologics (infliximab, adalimumab, ustekinumab and vedolizumab). The SUCRA ranking identified adalimumab (SUCRA = 0.81), infliximab (SUCRA = 0.80), vedolizumab (SUCRA = 0.79) and ustekinumab (SUCRA = 0.72) as the most effective treatments. The probability that thiopurines (SUCRA = 0.41), 5-ASA (SUCRA = 0.24), placebo (SUCRA = 0.16) and antibiotics (SUCRA = 0.08) were significantly higher weak.

Conclusion

This network meta-analysis confirms the efficacy of anti-TNF agents, vedolizumab and ustekinumab in preventing endoscopic CD POR without any difference between them. When prophylactic therapy is indicated, biologics appear as the best therapeutic option to prevent of endoscopic POR. Due to lower effectiveness, the use of 5-ASA and thiopurines should be limited in this situation.

Disclosure

Anthony BUISSON: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos/Alfa Sigma, GutyCare/Resilience, Janssen, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda, Tillotts. And Viatris. Lecture fees for Abbvie, Amgen, Biogen, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from: Abbvie, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Lessaffre, Lilly, Pfizer, Takeda.

Introduction

Colorectal cancer (CRC) is one of the most common neoplasms world widely. G-protein coupled receptors (GPCR) affect crucial elements of oncogenesis, such as responses to various endo- and exogenous stimuli (e.g. medications), angiogenesis and forming metastases. The magnitude of GPCR signaling is terminated by regulators of G-protein signaling (RGS), which typically possess GTPase activity. AXIN is an atypical RGS without GTPase function. Its main role is stabilization of β-catenin destruction complex in which it cooperates with adenomatous polyposis coli (APC) and glycogen synthase kinase3 (GSK3). Through this complex, AXIN antagonizes prooncogenic canonical Wnt signaling pathway that depends on β-catenin. On the other hand, recently attention has been paid to the potential tumor-suppressive properties of cannabinoids (CB) which are ligands of Gαi/o-type GPCR – CB1 and CB2.

Aims & Methods

In this project we aim to test the therapeutic potential of simultaneous targeting of AXIN and CB receptors with KYA1797K and WIN 55,212-2 in CRC cell lines (SW480, Caco-2) and non-cancerous enterocytes CCD 841 CoN as comparator. We hypothesize that KYA1797K is effective in monotherapy and in combination with cannabinoids in CRC. Moreover, we expect that stabilization of AXIN does not to weaken the effect of CB receptor ligands.
Cytotoxicity of KYA1797K (1; 10; 100, 300 µM) and WIN 55,212-2 (1; 10; 100 µM) in monotherapies and combined treatment (KYA1797K(10µM)+WIN 55,212-2(10µM) [K+W10] and KYA1797K(100µM)+WIN 55,212-2(10µM)) was assessed using MTT test. Relative genes’ expression was evaluated using quantitative real-time PCR and Western Blot. Statistical analysis included Shapiro-Wilk test, one-way ANOVA with post-hoc Dunnett’s and Tukey’s tests.

Results

Caco-2 cells were insensitive to KYA1797K in monotherapy excluding concentration of 300 µM, for which we observed significant cytotoxicity. Treatment with WIN 55,212-2 in concentration of at least 10 µM in both mono- and combined therapy significantly reduced viability of this cell line. Similar profile of changes was observed in SW480 line, however the strength of observed effect and sensitivity to KYA1797K were higher. In CCD 841 CoN cells significant additive effect of KYA1797K and WIN 55,212-2 was observed for 100 µM with no changes observed for 10 µM. Moreover, we found that treatment with K+W10 causes significant cytotoxicity in cancerous SW480 cells but not in normal enterocytes CCD 841 CoN. Moreover, K+W10 treatment resulted in increased expression of AXIN 1 and 2 in each cell line except AXIN 2 in Caco-2 line, in which opposite effect was observed. The combined treatment decreased CB1 receptors’ expression in all examined cell lines, whereas opposing tendency was observed for CB2. Furthermore, K+W10 treatment led to increased expression of RGS2, 11, APC and GSK-3. At the protein level K+W10 treatment surprisingly tended to decrease β-catenin relative expression. CB2 receptors were significantly more expressed in SW480 than in CCD 841 CoN that was consistent with cytotoxicity results.

Conclusion

AXIN stabilization is a promising new approach in CRC treatment. AXIN stabilization does not weaken CB1 and 2-dependent effects. The combined treatment of AXIN stabilizer and CB agonist may be especially important as life-prolonging therapy for patients with advanced CRC.

Clinical Case Summary

Syphilis is a sexually transmitted disease caused by the non-hepatotropic spirochete Treponema pallidum. Syphilitic hepatitis is rare complication from dissemination of these spirochetes to the liver either in the primary or secondary stages of infection. The mainstay of treatment for primary and secondary syphilis is a single injection of long-acting Benzathine penicillin G. However, patients who suffer from severe hypersensitivity reactions such as anaphylaxis with penicillin require alternative antibiotic therapies such as doxycycline. We present a case of a 43-year-old woman who presented to the emergency department with abdominal pain, nausea, and continued constipation after multiple treatment attempts. Her physical exam was remarkable for a diffuse, macular and pruritic rash that was noticed over the chest, arms, and legs; progressively worsening abdominal pain reported in the right upper and left lower quadrants; and bilateral tender inguinal lymph nodes, approximately 3 cm in size. The patient’s laboratory tests were significant for, elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase, hyperbilirubinemia, and positive quantitative RPR for syphilis. Ultrasound and CT of the abdomen and pelvis were both negative for any acute hepatic or cholecystitis findings. The patient was started on doxycycline due to a history of hypersensitivity allergic reactions from penicillin and experienced significant recovery of symptoms and aminotransferases on subsequent laboratory follow ups. Our case highlights a novel and unorthodox treatment strategy employed in the management of syphilitic hepatitis.

Clinical Case Summary

Schistosomiasis, is a major public health concern in endemic regions. While its primary manifestation is in the form of urogenital and intestinal infections, the ability of Schistosoma to mimic colorectal polyps poses a diagnostic challenge for gastroenterologists.
This is a case of a 48-year-old female patient from Lanao City with initial ultrasound and elastography findings suggesting liver parenchymal disease, mild splenomegaly and moderate liver fibrosis. Follow up ultrasound 3 years later showed a “lace-like” liver echo pattern and increasing splenomegaly. Proctosigmoidosocpy was done to document presence of schistosoma egss which appeared to be embedded on the muscularis layer. The patient was referred to the Department of Health for praziquantel treatment. Two years later, screening colonoscopy showed a sessile descending colon polyp measuring 0.5cm with regular tubular vessel surface pattern (JNET2A) removed via cold snare polypectomy. Histology of the polyp revealed still the presence of schistosoma eggs, just as the previous rectal mucosa biopsy. She completed a total of four cycles of Praziquantel treatment in the entire course of her illness.
This case reviews the clinical presentation, diagnostic modalities, and management strategies of Schistosoma presenting as colonic polyps, providing insights into the importance of considering parasitic infections in the differential diagnosis of colonic lesions.

References

1. Kay, G. L., Millard, P. S., Kay, C. J., & Kerrigan, D. D. (1995). Schistosoma japonicum presenting as colonic polyps: a case report and review of the literature. Journal of Clinical Pathology, 48(3), 276–278. https://doi.org/10.1136/jcp.48.3.276
2. Al-Khafaji, B. M., Yaghan, R. J., & Suh, O. J. (2006). Schistosomiasis presenting as colonic polyposis. Gastrointestinal Endoscopy, 64(3), 464–465. https://doi.org/10.1016/j.gie.2006.03.937
3. Adamthwaite, D. N., Patel, K. R., Mee, A. S., & Owen, R. G. (2004). Schistosomiasis: A rare cause of multiple colonic polyps. Histopathology, 45(6), 650–652. https://doi.org/10.1111/j.1365-2559.2004.02013.x
4. Al Hammadi, H., & Madani, M. A. (2014). Schistosoma mansoni: A rare cause of colonic polyposis. Saudi Journal of Gastroenterology, 20(2), 123–125. https://doi.org/10.4103/1319-3767.129469

Disclosure

none

Introduction

‘Inability to Belch’, also called retrograde cricopharyngeal dysfunction (R-CPD), is a syndrome characterized by inability or impaired ability to belch, gurgling noises from the chest or lower neck, thoracic or abdominal pain, bloating and flatulence (1). Although awareness of the disorder is increasing, little is known about its cause, characteristics or epidemiology.
Besides recognition of typical symptoms, high resolution impedance manometry (HRiM) is increasingly used to confirm the diagnosis in suspected cases (2, 3).

Aims & Methods

Our aim was to design a diagnostic questionnaire based on the cardinal symptoms, and to validate this questionnaire against the only available objective diagnostic tool at present, i.e. HRiM with belch provocation test (sparkling water) (2, 3).
The questionnaire was developed based on medical history taking of patients that presented to our center with ‘inability to belch’ (4). Fifteen symptoms were included: inability to belch, gurgling noises, thoracic pain, abdominal pain, nausea, fullness, early satiety, bloating, flatulence, heartburn, regurgitation, frequent or painful hiccups, dysphagia, and difficulty to vomit. These were questioned for frequency, severity, bothersomeness and the trigger or timing at which they occurred. A first draft of the questionnaire was evaluated in a cognitive debriefing of the first three R-CPD patients, after which some clarifying changes were made.
Subsequently, the questionnaire was filled out during HRiM prospectively by R-CPD and control patients, each of whom underwent belch provocation test as described by our group (3).
Wilcoxon signed rank test was used to compare between groups. A logistic model was used to compute probabilities with their 95% confidence interval (CI).

Results

The questionnaire was completed by 17 patients reporting inability to belch, and 47 control patients, during HRiM with belch provocation test. In 13 out of 17 patients (sensitivity 76%, positive likelihood ratio of HRiM: 8.44), R-CPD was confirmed with typical findings on HRiM. The indication for HRiM in control patients was GERD (n=27), dysphagia (n=9), chest pain (n=3), known achalasia (n=2), belching (n=1), globus (n=1) and dyspepsia (n=1). In the control patient group, 4 patients were excluded from further analysis because of abnormalities on HRiM similar to R-CPD (specificity 91%, negative likelihood ratio: 0.26).
Using HRiM as a gold standard, we identified the following questions that were significantly different in R-CPD patients vs. controls: frequency of inability to belch (p <0.001, probability of abnormal HRiM when present: 0.6000 CI 0.380:0.786 ), gurgling noises (p = 0.0019, probability when present 0.4000, CI 0.230:0.597), and dysphagia (p = 0.003, probability when present 0.065, CI 0.016:0.022). Even though these symptoms were often present in R-CPD, chest pain, abdominal pain, nausea, fullness, early satiety, bloating, heartburn, regurgitation, hiccups and vomiting did not differ significantly between both patient groups.

Conclusion

We designed a diagnostic questionnaire to help identifying R-CPD. Based on a comparison between R-CPD patients with a control population with a variety of upper motility disorders, the presence of ‘inability to belch’, gurgling noises; and the absence of dysphagia were significantly different between R-CPD patients and controls.
Pending further validation, this questionnaire provides a basis for developing a scoring system for patients with ‘inability to belch’ and it can be used to explore the epidemiology of this peculiar syndrome.

References

1. Bastian RW, Smithson ML. Inability to Belch and Associated Symptoms Due to Retrograde Cricopharyngeus Dysfunction: Diagnosis and Treatment. OTO Open. 2019;3(1):2473974x19834553.
2. Oude Nijhuis RAB, Snelleman JA, Oors JM, Kessing BF, Heuveling DA, Schuitenmaker JM, et al. The inability to belch syndrome: A study using concurrent high-resolution manometry and impedance monitoring. Neurogastroenterol Motil. 2022;34(5):e14250.
3. Karlien Raymenants FV, Stijn Arnaert, Jan Tack, Tim Vanuytsel, Filip Baert, Lieve Delsupehe, Joris Arts Manometric diagnosis and treatment of retrograde cricopharyngeus dysfunction (R-CPD). United European Gastroenterology Journal. 2023;11.
4. Arnaert S, Arts J, Raymenants K, Baert F, Delsupehe K. Retrograde Cricopharyngeus Dysfunction, a New Motility Disorder: Single Center Case Series and Treatment Results. J Neurogastroenterol Motil. 2024;30(2):177-83.

Introduction

Peroral endoscopic myotomy (POEM) has become a standard endoscopic treatment for patients with achalasia, with many studies reporting on its long-term effectiveness. However, the impact of a patient’s previous surgical history on the long-term outcomes of POEM remains unknown.

Aims & Methods

This study aims to compare the long-term efficacy of POEM in achalasia patients with and without prior surgical interventions. A single center, retrospective review was conducted on achalasia patients who underwent POEM between January 2016 to December 2020. Clinical, demographic, radiographic, endoscopic, and manometric data were collected. Patients with less than two years of follow-up without noted failure were excluded. The analysis compared outcomes between first-time POEM patients (naïve POEM) and those undergoing POEM following failed surgical treatments (redo POEM). The primary outcome was the clinical success rate, defined as an Eckardt Score of 3 or less at final follow-up and no need for additional interventions. Secondary endpoints included the prevalance of postoperative gastroesophageal reflux disesase (GORD), the necessity for acid suppression medications, and additional interventions for achalasia.

Results

Data were collected on 47 naïve POEM and 26 redo POEM patients. After excluding 17 naïve POEM patients and 8 redo POEM patients who did not meet the criteria for long-term follow-up, a total of 30 naïve POEM patients and 18 redo POEM patients were analyzed. In the redo POEM group, 77.8% (14/18) of the patients underwent Heller myotomy with Dor fundoplication, while the surgical details for the remaining patients were unknown. The median length of symptoms was 5 (IQR 3-10) years for naïve patients and 6 (IQR 1.2-17.5) years for redo patients (p=0.29). According to the Chicago classification v4.0, the achalasia subtypes in the naïve POEM group were Type I in 9 patients (30%), Type II in 12 (40%), Type III in 3 (10%), and other types in 6 (20%). For the redo POEM group, subtypes were Type I in 9 patients (50%), Type III in 2 (11.1%), and unspecified in 7 (38.9%). Barium esophagram revealed no significant differences in the maximum diameter between the groups (naïve POEM 45.8 ± 21.4 mm vs. redo POEM 44.9 ± 15.4 mm, p=0.89). Long-term success rates were 76.7% (23/30) in naïve POEM and 83.3% (15/18) in redo POEM, with no significant difference between the groups (p=0.72). Postoperative GORD was noted in 63.3% (19/30) in the naïve POEM versus 67% (12/18) in the redo POEM (p=0.06), with newly prescribed acid suppression medication in 23.3% (7/18) and 55.6% (10/18), respectively (p=0.02). Additional interventions for achalasia were required in 10% (3/30) in the naïve POEM versus 11.1% (2/18) in the redo POEM, with no significant difference between the groups (p=1.0). In the naïve POEM group, one patient required a second POEM, another was hospitalized due to achalasia recurrence, and a third underwent Heller myotomy with Dor fundoplication. In the redo POEM group, one patient underwent endoscopic balloon dilatation, and another required esophagectomy.

Conclusion

POEM is an effective long-term treatment for achalasia, demonstrating similar success rates in patients undergoing either their first or redo POEM procedures. The overall efficacy and safety profiles support POEM as a recommended treatment for managing achalasia regardless of prior surgical treatment failures.