Introduction

Per-oral endoscopic myotomy (POEM) is highly effective in the short-term management of achalasia, with recent studies showing durable success.^1,2 The aim of this study was to evaluate long term clinical outcomes of POEM for oesophageal motility disorders, in a tertiary portuguese center.

Aims & Methods

This was a retrospective single center cohort study, from prospective collecting data, of consecutive patients who underwent POEM between January 2017 and February 2021, with a minimum of 24 months follow-up. Clinical response was defined by an Eckardt score ≤ 3. Gastroesophageal reflux was assessed through clinical interview and endoscopy.

Results

A total of 72 patients underwent POEM with technical success, during the specified study period. Nine (12.5%) were lost to follow-up before at least 24 months. Of the remaining 63 patients, 57% were female, median age was 54 years (range 17-79) and 41.3% had prior treatments. Indication for intervention was achalasia in 62 patients (type 1, n=18; type 2, n=36; type 3, n=7; one non-specified) and esophagogastric junction outflow obstruction in one, with preoperative median Eckardt score of 6 (range 2-11). Median follow-up duration was 42 months (range 24-63). Clinical response at one month was achieved in 61 patients (96.8%). Of the patients with initial response, clinical response at last follow-up was 90.2%. In the long term, six patients required additional treatment, with median symptom relapse at 35.5 months (range 12-48). Two patients underwent re-poem with clinical response. Gastroesophageal reflux symptoms were reported in 27.9%, with 68.9% maintaining daily proton pump inhibitor therapy at last follow-up. Endoscopic evaluation was performed in 46 patients, showing reflux esophagitis in 22.

Conclusion

POEM is an effective therapy for achalasia, with durable success rate and possible reintervention in case of relapse. Gastroesophageal reflux is a common late adverse event. Studies with longer follow-up are needed to determine long term effectiveness and reflux exposure risk.

References

1 – Brewer Gutierrez OI, et al. Long-term outcomes of per-oral endoscopic myotomy in achalasia patients with a minimum follow-up of 4 years: a multicenter study. Endoscopy International Open. 2020 April; 08(05):E650—E655. https://doi.org/10.1055/a-1120-8125
2 - Modayil RJ, et al. Peroral endoscopic myotomy: 10-year outcomes from a large, single-center U.S. series with high follow-up completion and comprehensive analysis of long-term efficacy, safety, objective GERD, and endoscopic functional luminal assessment. Gastrointestinal Endoscopy, vol. 94, 5. 2021 May. https://doi.org/10.1016/j.gie.2021.05.014

Introduction

By 2030, pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related death. Due to its resistance to conventional therapies and heterogeneous mutational landscape, molecular stratification and the development of targeted therapeutic options are essential for improving survival of PDAC patients. Previous work from our group investigated loss-of-function mouse models for the ATM serine/threonine kinase causing homologous recombination deficiency (HRD) in PDAC. Specifically, ATM loss was reported to accelerate tumorigenesis, support metastatic burden, and coincide with oncogenic programs, including epithelial-mesenchymal transition (EMT). Interestingly, ATM-deficient tumors accumulated EZH2, suggesting that ATM status contributes to rewiring the epigenetic landscape of pancreatic tumors, subsequently supporting oncogenic features.

Aims & Methods

To investigate whether and how EZH2 impacts ATM-deficient PDAC pathogenesis, we generated conditional double ATM and EZH2 knockouts in Kras^G12D/+; Ptf1a^Cre/+ mice. In vitro approaches were conducted using primary cell lines isolated from murine endpoint tumors. Additionally, CRISPR/Cas9 strategy was implemented on ATM-deficient cell lines to decipher the ATM-EZH2 molecular axis.

Results

Double-null mice showed extended mouse survival and decreased undifferentiated malignant cell features. Strikingly, interrogation of publicly available human datasets (TCGA, PanCancer Atlas) revealed a significant extended progression-free survival of ATM^neg EZH2^neg PDAC patients compared to ATM^neg EZH2^pos PDAC cases. Furthermore, we identified the histone-methyltransferase EZH2 as a direct ATM substrate impacting the mesenchymal phenotype of ATM-depleted tumors. Interestingly, RNA-seq analysis of ATM-deficient pancreatic cancer cells revealed upregulation of a transcriptomic program associated with cell differentiation upon EZH2 depletion by CRISPR/Cas9 strategy. In line, EZH2 depletion restored differentiated tumor features ex vivo. Further in vitro investigations revealed that ATM status significantly impacts EZH2 activity via a post-translational regulation axis, leading to a fostered tumor supporting EZH2 activity during pancreatic carcinogenesis. Specifically, the ATM kinase activity results in EZH2 ubiquitination and degradation by promoting Cullin1 E3-ubiquitin ligase recruitment. Finally, we demonstrated that a combinatorial therapy involving a potent EZH2 inhibitor promotes genomic instability and exacerbates the cytotoxic effects of PARP interference in ATM-deficient HRD PDAC.

Conclusion

Overall, we show that ATM deficiency significantly impacts EZH2 epigenetic functions and highlight the molecular stratification according to ATM status prior to pharmacological EZH2 interference in PDAC therapies as a valuable approach to target ATM-deficient HRD tumors.

Introduction

We lack reliable biomarkers to identify patients with inflammatory bowel disease (IBD) at a greater risk of severe disease course. With emerging evidence that early step-down treatment in severe patients leads to better disease outcomes, alongside worries about overtreatment of mild patients, there is a clinical need to identify such biomarkers.

Aims & Methods

In this study, we explore genetic variants associated with severe disease course for ulcerative colitis (UC) in a nationwide cohort of 4491 patients from Denmark.
We genotyped 4491 patients with UC (4153 from Danish birth blood spot archive; 338 from NorDIBD regional cohort), linking them with registry data capturing medical interactions throughout patients’ lifetimes. Patients who required 2+ IBD-related hospitalizations, 2+ IBD-related major surgeries, 1 IBD-related hospitalization and 1 IBD-related major surgery or use of systemic corticosteroids (≥5000 mg) in the first 3 years of diagnosis were defined as severe. We conducted a genome-wide association study comparing severe patients (N=1203) to those with a less severe disease course (N=3288).

Results

The GWAS identified a signal within the HLA region, with the HLA-DRB1*01:03 allele driving the association (OR=3.30 [2.23-4.87], P=2.08×10^-9, UC carriage rate=2.8%). We did not observe an association with CD severity in a similarly ascertained cohort of 3688 individuals (P=0.79).
Remarkably, carriage of DRB1*01:03 was associated with a seven-fold increase of major surgery risk (OR=7.05 [4.55-10.91], P=2.31×10^-16) (Table 1). At the point of diagnosis, carriage of DRB1*01:03 was associated with higher CRP levels (β=2.68, P=1.70×10^-7), f-cal levels (β=1.92, P=4.42×10^-3) and a higher rate of hospitalization at diagnosis (OR=1.64, P=0.014), suggesting that the effect on severity is not limited to disease progression.

Conclusion

In this large-scale, unselected nationwide cohort study, we find that HLA-DRB1*01:03 is a biomarker of UC disease course that is associated with a more severe presentation at diagnosis, as well as higher subsequent risk of surgery and hospitalization. Demonstrating the association at a genome-wide significance level for the first time, this study revitalizes findings from smaller studies at the beginning of the genetic era which explicitly recruited severe patients and made estimating carriage effects difficult.
While HLA-DRB1*01:03 is a low-frequency allele, patients who carry it are at a much higher risk of severe UC. As the cost of typing a single HLA allele is low (under 50 EUR) and several pharmacogenetic variants are beginning to be tested at diagnosis, we argue that it is a valuable addition to the arsenal of personalized healthcare tools.

Introduction

Intestinal ultrasound (IUS) is a non-invasive, reproducible, low-cost technique for the assessment of intestinal diseases.¹
Crohn's disease (CD) and irritable bowel syndrome (IBS) are two of the major causes of chronic diarrhoea and abdominal pain in high-income countries.² IBS, especially in the diarrheal (IBS-D) or mixed (IBS-M) variants, has clinical features similar to those of CD.
The role of IUS in the diagnosis and monitoring of CD is well established,^{3, 4} whereas only scanty data are available on IBS. Current IBS guidelines do not recommend the use of IUS even to distinguish between IBS-D or IBS-M and CD.^{5, 6}

Aims & Methods

The aim of this two-gate diagnostic study was to assess the accuracy of IUS in discriminating between IBS-D or IBS-M and CD in patients presenting with similar symptoms.
In a high-volume tertiary Centre, consecutive patients symptomatic for chronic diarrhoea and abdominal pain underwent IUS performed by three experienced gastroenterologists.
In the group with clinically active CD, patients had a previous diagnosis based on clinical, biochemical, endoscopic, radiologic and histologic criteria, while in the IBS group subjects had a previous diagnosis based on Rome IV Criteria.
Bowel wall thickness (BWT) of the terminal ileum, ascending colon, transverse colon and descending colon/sigma was evaluated using two cut-offs of 3 mm and 4 mm.⁷ Enlarged lymph nodes, mesenteric fat hypertrophy, bowel wall stratification and submucosal vascularity were also assessed.
The diagnostic accuracy of IUS in discriminating between the two groups was estimated in terms of sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and overall accuracy (OA) (Table 1).

Results

A total of 50 patients with IBS (62% female, mean age 41 years, SD ± 13 years, 54% IBS-D) and 50 subjects with CD (44% female, mean age 47 years, SD ± 17 years) were enrolled.
Forty-nine patients with IBS (98%) and 8 patients with CD (16%) and had a BWT < 3 mm. 49 patient with IBS (98%) and 12 patients with CD (24%) had a BWT < 4 mm.
Sensibility, specificity, LR+ and LR- of BWT < 3 mm were 98%, 84%, 6.13 and 0.02, respectively.
Sensibility, specificity, LR+ and LR- of BWT < 4 mm were 98%, 76%, 4.08 and 0.03, respectively.
BWT with 3 mm and 4 mm cut-offs showed an OA in discriminating between CD and IBS-D or IBS-M of 91% and 87%.
The absence of altered IUS parameters had 94% OA in discriminating between CD and IBS (Table 1).

Conclusion

IUS seems able to discriminate between IBS-D or IBS-M and CD in patients with chronic diarrhoea and abdominal pain. Particularly, a BWT < 3 mm may rule out the presence of clinically active CD and support the diagnosis of IBS. On the other hand, a BWT > 3 mm or a single altered ultrasound parameter might raise suspicion of CD and justify further testing. Cross-sectional studies are needed to confirm these preliminary results.

References

[1] Bryant RV, et al. Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application. Gut 2018;67(May (5)):973–85.
[2] Arasaradnam TP, et al. Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition. Gut vol. 67,8 (2018): 1380-1399.
[3] Castiglione F, et al. Noninvasive diagnosis of small bowel Crohn’s disease: direct comparison of bowel sonography and magnetic resonance enterography. Inflamm Bowel Dis 2013;19:991–8.
[4] Maaser C et al. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. Journal of Crohn's & colitis vol. 13,2 (2019): 144-164.
[5] Vasant, Dipesh H et al. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut vol. 70,7 (2021): 1214-1240.
[6] Savarino E et al. “Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility.” United European gastroenterology journal vol. 10,6 (2022): 556-584.
[7] Fraquelli M, et al. Role of US in detection of Crohn disease: meta-analysis. Radiology. 2005;236(1):95-101.

Introduction

Low Phospholipid-Associated Cholelithiasis (LPAC) syndrome is a rare disorder caused by mutations in the ABCB4 phospholipid transporter, found in biliary canaliculi. These mutations lead to a deficiency in phospholipids and the subsequent precipitation of cholesterol crystals within the small intrahepatic bile ducts. LPAC syndrome can be diagnosed following the emergence of biliary symptoms or through familial screening. The objective of our study is to characterize the epidemiological, clinical, and paraclinical data of patients monitored for LPAC syndrome in our institution and to assess therapeutic responses and outcomes.

Aims & Methods

We collected data from all patients diagnosed with LPAC syndrome at our institution. Diagnosis was established based on the presence of at least two of the following criteria: (1) age at onset of biliary symptoms ≤40 years; (2) presence of hyperechoic intrahepatic foci ("comet tails" or micro-spots); (3) recurrence of biliary symptoms post-cholecystectomy.

Results

10 patients were included. The Average age at diagnosis was 33,6 years, with symptoms typically beginning around age 30. The sex ratio was 2/8 (M/F).a family history of biliary lithiasis and cholecystectomy before the age of 40 were found in 70% of cases . None of the female patients had a history of pregnancy-related cholestasis. 70% of the patients had undergone cholecystectomy prior to their LPAC diagnosis, with recurrence of biliary symptoms before age 40 in all these patients. Clinical presentations upon admission included symptomatic gallstone disease in 5 cases, acute cholangitis due to main bile duct stones in 4 cases, and acute lithiasic pancreatitis in 1 case. Hepatobiliary ultrasound was performed in all patients, revealing comet tail signs in 50% of cases, hyperechoic intrahepatic spots in 20% of cases, and intrahepatic stones in 50% of cases. Biochemical tests showed hyperbilirubinemia in 30% of cases, elevated Gamma-GT and alkaline phosphatase in 80% of cases, and hepatocellular damage in 40% of cases. A mutation in the ABCB4 gene was found in 2-patients.8 patients benefit from An Ursodeoxycholic Acid (UDCA) dosage averaging 11mg/kg, experiencing significant clinical and biological improvements.

Conclusion

LPAC syndrome is a rare pathology in our series, predominantly affecting young, non-overweight women with personal and family history of early biliary stones occurrence . Treatment with Ursodeoxycholic Acid (UDCA) controlled symptoms in the majority of cases.