Introduction

Intestinal microbiota are prominent in the etiology of irritable bowel syndrome (IBS). In this exploratory study, we investigated short- and long-term changes in the microbiota of IBS patients after intervening with a low-FODMAP diet (LFD) or probiotics (an 8 strains lactobacilla) using a standardized microbiota characterization test intended for routine use.

Aims & Methods

We analyzed data and fecal samples collected in a previous trial from non-comorbid IBS patients before treatment, and then again after four weeks and one year of treatment. Response to treatment was defined by a reduction in the IBS-SSS score, and the gut microbiota were characterized using the standardized and GA-map® Dysbiosis Test Lx.

Results

Of the 25 responders to either treatment, two of the 22 with fecal samples available were dysbiotic at baseline, increasing to eight out of 19 after four weeks; after one year all responders providing a sample were normobiotic (n=15). After four weeks, the abundance of Bacilli, Lactobacillus spp. and Streptococcus salivarius ssp. thermophilus were temporarily increased in the probiotic responder group (p<0.05), while for LFD responders Anaerobutyricum hallii had decreased. There was a greater abundance of R. gnavus at baseline in those responding to probiotics than in those responding to LFD.

Conclusion

In addition to improving IBS symptoms, sustained LFD or repeat probiotics tended to temporarily alter the microbiota profile in responders. Microbiota characterization is a promising tool for monitoring IBS treatments; however, more extensive studies are needed.

Disclosure

Marwah Al-sheikh, Dorit Vedel Ankersen and Mette Bennedsen declare no conflict of interest
Christina Casén is an employee of Genetic Analysis AS and owns stocks and shares in Genetic Analysis AS.
Kristin Gravdal and Graceline Tina Kirubakaran are employees of Genetic Analysis AS.
Johan Burisch reports personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, personal fees from Galapagos, outside the submitted work.
Pia Munkholm has received consulting or lecture fees from AbbVie, Calpro A/S, Ferring Pharmaceuticals, Jansen-Cilag, Celgene, Takeda, Tillotts Pharma, Merck Sharp & Dohme, Pfizer, and research funds from Coloplast, Ferring Pharmaceuticals, Jansen-Cilag, Merck Sharp and Dohme, Pharmaforce, Svar A/S, Takeda, Tillotts Pharma, Novo Nordic.

Introduction

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common gastroenterological emergency associated with significant morbidity and mortality [1-3]. Upper gastrointestinal endoscopy is currently recommended as the gold standard modality for both diagnosis and treatment [4]. As historically played a limited role in the diagnosis of acute NVUGIB, multidetector-row computed tomography angiography (MDCTA) is emerging as a promising tool in the diagnosis of NVUGIB, especially for severe cases [5-6]. However, to date, evidence concerning the role of MDCTA in the NVUGIB diagnosis is still lacking.

Aims & Methods

The purpose of this study was to retrospectively investigate the diagnostic performance of emergent MDCTA performed prior to any diagnostic modality or following urgent upper endoscopy to identify the status, the site and the underlying etiology of severe NVUGIB. Institutional databases were reviewed in order to identify severe acute NVUGIB patients who were admitted to our bleeding unit and were referred for emergent MDCTA prior to any hemostatic treatment (<3 hours) or following (<3 hours) endoscopy, between December 2019 and October 2022. The study aim was to evaluate the diagnostic performance of MDCTA to detect the status, the site and the etiology of severe NVUGIB with endoscopy, digital subtraction angiography, surgery, pathology or a combination of them as reference standards.

Results

A total of 68 patients (38 men, median age 69 years [range 25–96]) were enrolled. The overall MDCTA sensitivity, specificity, and accuracy to diagnose bleeding status were 77.8% (95% CI: 65.5-87.3), 40% (95% CI: 5.3-85.3), and 75% (95% CI: 63.0-84.7), respectively (Table 1). Finally, the overall MDCTA sensitivity to identify the bleeding site and the bleeding etiology were 92.4% (95% CI: 83.2-97.5) and 79% (95% CI: 66.8-88.3), respectively.

Table 1. The diagnostic performance of MDCTA in detecting bleeding status.

Conclusion

MDCTA seems to be a feasible and effective modality in detecting the site, the status and the etiology of severe acute NVUGIB. It may play a crucial role in the management of selected cases of NVUGIB, especially those clinically severe and/or secondary to rare and extraordinary rare sources, effectively guiding timing and type of treatment. However, further large prospective studies are needed to clarify the role of MDCTA in the diagnostic process of acute NVUGIB.

References

1. Wuerth BA, Rockey DC. Changing Epidemiology of Upper Gastrointestinal Hemorrhage in the Last Decade: A Nationwide Analysis. Dig Dis Sci 2018; 63: 1286–1293.
2. Laine L, Yang H, Chang S-C, et al. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol 2012; 107: 1190–1195; quiz 1196.
3. Sanders DS, Perry MJ, Jones SGW, et al. Effectiveness of an upper-gastrointestinal haemorrhage unit: a prospective analysis of 900 consecutive cases using the Rockall score as a method of risk standardisation. Eur J Gastroenterol Hepatol 2004; 16: 487–494.
4. Gralnek IM, Stanley AJ, Morris AJ, et al. Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021. Endoscopy 2021; 53: 300–332.
5. Napoli A, Fleischmann D, Chan FP, et al. Computed tomography angiography: state-of-the-art imaging using multidetector-row technology. J Comput Assist Tomogr 2004; 28 Suppl 1: S32-45.
6. Wu L-M, Xu J-R, Yin Y, et al. Usefulness of CT angiography in diagnosing acute gastrointestinal bleeding: a meta-analysis. World J Gastroenterol 2010; 16: 3957–3963.

Disclosure

No conflict of interest to declare.

Introduction

STW5-II is a medicinal product composed by 6 herbal extracts that has been shown to relieve clinical symptoms in patients with dyspepsia. The mechanisms of action include selective effects on gastric tone, antro-pyloric activity
and visceral sensitivity. Patients with functional dyspepsia (FD) have a poor tolerance to gastric gas that has been related to a combination of several factors, including delayed gas transit and evacuation, visceral hypersensitivity and altered viscero-visceral reflexes.

Aims & Methods

The aim of the present study was to determine the effect of STW5-II on transit and tolerance of gastric gas in patients with FD. In 27 patients (26 female and 1 male, age range 22-70 years old) with FD and bloating (17 postprandial distress syndrome, 4 epigastric pain syndrome and 6 mixed type dyspepsia), a gas challenge test was performed after two weeks on STW5-II 20 drops t.i.d. or placebo, in a parallel, double blinded, controlled trial. The gas challenge test consisted in infusion of a mixture of gases into stomach through a nasogastric tube at 100 mL/min for 15 minutes (total volume infused 1500 mL) with concomitant gastric nutrient perfusion (Nutridrink 1.5 Kcal/ml, total 315 Kcal), mimicking a normal meal. Rectal gas evacuation, via a rectal tube connected to a barostat, and belching, by an esophageal multilumen impedance catheter, were continuously measured for 90 min from infusion start. Abdominal symptoms, using a 0-6 perception scale, and abdominal distension, using a tape measure, were quantified at 10-min intervals.

Results

Gastric gas infusion was followed by a progressive gas evacuation from the rectum, that was accelerated when patients were on STW5-II, compared to placebo. After 20 min from infusion start (when gas and nutrient perfusion was already finished) only 80±39 mL of gas had been expelled in studies on placebo, whereas 319±81 mL of gas were collected on STW5-II group (p=0.015). Thereafter, both groups continued to expel gas at similar rates, without differences between groups at the end of the study (837±180 mL and 1030±160 mL, saline and STW5-II, respectively; p=0.432). Gastric belches were exceptional in both groups (0.8±1.0 and 1.1±1.6 gastric belches in 90 min, saline and STW5, respectively; p=0.318).
Gastric gas infusion gas associated to a rapid rise in perception of abdominal symptoms, that was significantly lower in patients treated with STW5-II than those treated with placebo (score increment 3.0±0.4 vs 1.9±0.6, placebo and STW5-II, respectively; p=0.036). Following continuous rectal gas evacuation, perception decreased in both groups, however perception remained significantly greater at the end of the 90-min study period in patients on saline (score increment 1.4±0.6; p=0.018 vs infusion start), whereas it had returned to basal levels in patients treated with STW5-II (score increment -0.2±0.4; p=0.324 vs infusion start). There were no significant differences in abdominal girth increment between groups (max increment 16±2 mm and 13±2 mm placebo and STW5-II, respectively; p=0.224).

Conclusion

STW5-II is a medicinal product that improves tolerance to gastric gas in patients with functional dyspepsia, by acceleration of transit and rectal evacuation of gas, and reduction of the intensity of symptoms elicited by gas. Hence, this medicinal product could be beneficial for management of gas-related abdominal symptoms like bloating in patients with functional dyspepsia.
EudraCT: 2019-003976-38

Introduction

The sex differences in the incidence of gastric cancer have been well known. However, uncertainty still exists in terms of prognosis of GC. For example, the US SEER data reports a significantly better prognosis in females than in males, but the prognosis is better in males than in females in Korean Central Cancer Registry data. Roles of molecular markers and gut microbiota as new prognostic factor are emerging recently, but few studies seem to try to reveal sex differences.

Aims & Methods

In this background, we aimed to analyze the differences in GC characteristics according to sex in Korean patients, mainly focused on survival. This was a single-center retrospective study. A total of fifteen thousand patients diagnosed with GC at the Seoul National University Bundang Hospital between 2003 and 2023 were included. Clinicopathological characteristics, histologic types, survival rates with age- and stage-stratification, and associated risk factors were analyzed. Information related to death was cross-verified using medical record review and data from the National Statistical Office.

Results

The ratio of males and females was about 2:1, and there was no differences in stage between sexes. Female patients were significantly younger than males, had more gastric body cancers and tumors with diffuse type or poorly differentiated histology. Females underwent less endoscopic treatment and more surgery, and tumors with microsatellite instability was more common in females, while mutation of p53 was less common. In histological types according to Lauren classification, diffuse type histology was more common in younger patients in both males and females. The proportion of intestinal type GC increased with age, but the proportion increased rapidly in males while increased gradually in females. In Cox multivariate regression analysis for GC-related death, older age, proximal tumor location, diffuse type histology and advanced tumor stage were risk factors. In terms of survival, overall and GC-specific survival did not show significant differences between sexes in the analysis of the total population. However, sex differences in survival reversed with age, that younger females under 50 showed survival disadvantages, but the survival became similar in 50s, and older females over 60 showed survival advantages in both overall and GC-specific survival. Furthermore, in the stratification analysis according to the stage, there were no significant differences in stages I to III. But, stage IV female patients showed significant survival disadvantages. In subgroup analysis of stage IV patients, the differences between males and females in median survival were two months, and female patients were significantly younger and had a higher proportion of diffuse type GC than male patients, which shows aggressive feature and is related to poorer survival.

Conclusion

Significant differences in survival between sexes were observed with stratification analysis, although sex itself was not an independent prognostic factor. These age-dependent changes are thought to suggest the effect of sex hormones. These differences should be considered in clinical practice and later research in terms of tailored medicine.

Introduction

Postoperative ileus, is one of the most common causes of prolonged hospital stays after abdominal surgery which cause from physiologic hypomotility of the gastrointestinal tract occurring immediately after abdominal surgery. Multi-modal approach to the resolution of postoperative ileus includes ERAS protocol such as opioid minimization, early ambulation, intake of prokinetic drug. Mosapride citrate (mosapride) is known to promote gastrointestinal motility. The objective of this study is to evaluate the effects of mosapride on postoperative ileus and postoperative gastrointestinal motility in patients undergoing elective open and laparoscopic colorectal surgery.

Aims & Methods

The study was approved by ethics committee of the Faculty of Medicine Ramathibodi Hospital Mahidol University (Ref. Number COA.MURA2021/328,ClinicalTrials.gov Identifier: NCT04905147). Forty-four colorectal cancer patients, undergoing open and laparoscopic colorectal surgery in Ramathibodi Hospital during July 2021-August 2022, were randomly assigned to a mosapride group or control group. The mosapride group received 15 mg of mosapride by enteric route with 50 ml of water three times a day, starting on postoperative day 1. The control group received 15 mg of placebo drug with 50 ml of water at the same time. Postoperative time to the first passage of flatus and the first bowel movement were evaluated by one investigator with triple blind study. Time to step diet, length of postoperative hospital stays, and adverse effects were also evaluated in secondary outcomes.

Results

All forty four patients were include, twenty-three in control group and twenty-one in mosapride group. There were no statistically significance differences between mean age and type of surgery (laparoscopic or open) in two group (P>0.05). Time to first bowel movement and time to passage of flatus after operation were significantly shorter in the mosapride group than the control group (26 vs 50 hours, P=0.004 and 40 vs 70 hours, P=0.003, respectively). Time to step diet (soft diet) was also shorter in the mosapride group (90 vs 132 hours, P=0.004). Time to defecate was less in mosapride group than control group (80 vs 120 hours, P <0.001). Length of hospital stay was significantly shorter in patients receiving mosapride (7 vs 10 days, P=0.004).

Conclusion

This study demonstrated the efficacy of mosapride when administered to patients who underwent elective colorectal surgery. Mosapride significantly enhance recovery of gastrointestinal motility and shorter length of hospital stay with no significant adverse effects.

References

1. Collins TC, Daley J, Henderson WH, Khuri SF. Risk factors for prolonged length of stay after major elective surgery. Ann Surg 1999;230:251–9
2. Vather R, O'Grady G, Bissett IP, Dinning PG. Postoperative ileus: mechanisms and future directions for research. Clin Exp Pharmacol Physiol. 2014;41(5):358-370.
3. Goldstein JL, Matuszewski KA, Delaney C, Senagore A, Chiao E, Shah M, et al. Inpatient economic burden of postoperative ileus associated with abdominal surgery in the United States. P AND T.2007;32(2):82.
4. Venara A, Neunlist M, Slim K, Barbieux J, Colas PA, Hamy A, et al. Postoperative ileus: Pathophysiology, incidence, and prevention. J Visc Surg 2016;153:439-46.
5. Luckey A, Livingston E, Taché Y. Mechanisms and Treatment of Postoperative Ileus. Arch Surg. 2003;138(2):206–214.
6. Georgiadis, G & Markantonis, Sophia & Triantafillidis, John. (2000). Prokinetic agents: Current aspects with focus on cisapride. Annals of Gastroenterology. 13.
7. Reynolds, J.C. & Putman, P.E. (1992) Prokinetic Agents, Gastroenterol Clin of North Am, Vol.21, pp.567-596.
8. Taniyama, K., Makimoto, N., Furuichi, A. et al. Functions of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine₄ receptor, in gastrointestinal motility. J Gastroenterol 35, 575–582 (2000).

Introduction

The complex signalling pathways of thyroid hormones (TH) has been recently involved in the liver diseases pathogenesis. Particularly, it has been proven that the expression of deiodinases type-1 and 3 (D1-3) changes during liver injury, but their role is still poorly understood in hepatocarcinogenesis process.

Aims & Methods

We aimed to evaluate the role of TH signalling pathway in liver carcinogenesis. In this prospective study, 49 patients underwent liver surgery for HCC in cirrhosis (31 cases) or for other non-neoplastic indication in non-cirrhotic context (18 controls). We evaluated genes and protein expression of the main TH metabolism factors (D1, Monocarboxylate transporter-MCT8, Thyroid receptors-TR alpha and beta, Kruppel-like factor-KLF-9 and TH-responsive SPOT-14 gene), with RT-PCR and Western blot analysis in HCC, cirrhotic tissue and healthy liver samples.

Results

RT-PCR analysis showed a progressive statistically significant decrease of D1 (p=0.003), MCT-8 (p=0.001), and TRβ (p=0.04) mRNA expression from healthy liver to HCC. The expression of KLF9, involved in cell differentiation and proliferation, decreased accordingly (p=0.01). Similarly, the expression of SPOT14 decreased in relation to reduced TH activation (p=0.009). Western Blot analysis showed a decreased expression of D1 protein in all cirrhotic samples (p=0.01), while D3 increased in 50% of HCC (p=0.02). Among HCC patients, D3 expression was associated with poor tumor differentiation compared to D3 negative HCC subjects (p=0.007). Furthermore, at Kaplan-Meyer analysis, overall survival of D3 positive HCC was significantly lower than D3 negative HCC (p=0.04).

Conclusion

These preliminary data showed that D3 expression could define a more severe phenotype of HCC with poor tumor differentiation and reduced survival. Moreover, the signalling pathway of TH is dysregulated in HCC, with intrahepatic hypothyroidism. However, these results need to be confirmed in large cohorts.

Introduction

Thiopurines are one of the major drugs for inflammatory bowel disease. In Asian individuals, the SNP p.Arg139Cys in exon 3 of NUDT15 is associated with leucopenia and hair loss.

Aims & Methods

The aims of this study are to evaluate the long-term effects of NUDT15 on clinical outcomes.
The patients (ulcerative colitis130, Crohn’s disease 55 cases) were divided into the mutant and the wild group of NUDT15, and the daily dosage of thiopurines and the effect of the mutation on hospitalization and surgery were investigated.

Results

Compared to the mutant group (n = 48), the daily thiopurine dosage increased in the wild group (n = 137)(p = 0.024). The time to dose reduction and discontinuation of thiopurine was significantly shorter in the mutant group, respectively (p < 0.001, p = 0.039). The mutant group tended to have more hospitalizations (p = 0.067), and surgeries were significantly more frequent (p = 0.028). In ulcerative colitis, thiopurine discontinuation was associated with hospitalization and surgery, respectively (p = 0.003, HR 2.87, 95% CI 1.44 - 5.71, p = 0.036, HR 5.45, 95% CI 1.12 - 26.5). In Crohn's disease, the presence of SNPs was associated with hospitalization (p = 0.019, HR 3.68, 95% CI 1.24-10.97) and surgery (p = 0.036, HR 6.81, 95% CI 1.14 - 40.86).

Conclusion

In ulcerative colitis, it is important to continue thiopurine with fine-tuning of the dosage to avoid hospitalization and surgery. In Crohn's disease, a direct association between the NUDT15 SNP and hospitalization and surgery was demonstrated.

References

1. Yang, S. K. et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 46, 1017-1020, doi:10.1038/ng.3060 (2014).
2. Kojima, Y. et al. Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines. World J Gastroenterol 24, 511-518, doi:10.3748/wjg.v24.i4.511 (2018).
3. Coenen, M. J. H. et al. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology 149, 907-917.e907, doi:10.1053/j.gastro.2015.06.002 (2015).
4. Hirotsu, Y. et al. Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next-generation sequencing. Mol Genet Genomic Med 3, 121-129, doi:10.1002/mgg3.120 (2015).
5. Sakamoto, I. et al. BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. Cancer 122, 84-90, doi:10.1002/cncr.29707 (2016).
6. Hirotsu, Y. et al. Intrinsic HER2 V777L mutation mediates resistance to trastuzumab in a breast cancer patient. Med Oncol 34, 3 (2017).
7. Hirotsu, Y. et al. Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer. Mol Genet Genomic Med 3, 459-466 (2015).

Disclosure

The authors have no conflict of interest to declare. All co-authors have seen and agree with the contents of the manuscript, and there is no financial interest to declare.