Clinical Case Summary

MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) is a rare mitochondrial disorder characterized by multisystem involvement, particularly in the neurological, cardiovascular, and gastrointestinal (GI) systems. GI manifestations are less commonly discussed but can present significant clinical challenges, including dysmotility, bowel ischemia, and obstruction.
A 19-year-old male, with a family history of MELAS affecting multiple relatives, was admitted with status epilepticus and other associated neurological and cardiovascular symptoms. On admission, the patient exhibited severe metabolic acidosis and elevated lactate levels, raising suspicion for mitochondrial dysfunction. During his ICU stay, he was found to have significant GI symptoms, including a post-operative ileus likely secondary to dysmotility syndrome associated with MELAS. He was subsequently diagnosed with a faecal bezoar causing large bowel obstruction (LBO) in the sigmoid colon, requiring laparotomy with disimpaction of the faecal mass, and decompression of the small and large bowel. There was evidence of bowel ischemia during the surgical exploration, with friable mucosa and necrotic areas observed in the proximal rectum and descending colon. Fortunately, all bowel sections were viable after decompression, and no further ischemic damage was noted.
This case highlights the importance of considering gastrointestinal complications, such as fecal bezoars and bowel ischemia, in patients with MELAS syndrome. GI manifestations, though less commonly recognized, can lead to significant clinical issues such as bowel obstruction and ischemic damage. Early intervention, including surgical management and decompression, is crucial to preventing further complications. Awareness of these potential issues is essential for clinicians managing patients with MELAS, as prompt treatment can improve outcomes and mitigate the risk of severe long-term GI dysfunction.

References

1. Colonoscopy images of diffuse friable mucosa with necrosis in sigmod colon and descending colon

Clinical Case Summary

We report a case of Intrahepatic Cholestasis of Pregnancy (ICP) leading to a rejections of a living, related donor liver two years after the liver transplantation (LT). The 36yo patient underwent LT in November 2021 in Mongolia due to a HBV/HDV related liver cirrhosis. Until August 2024, she had normal test results when she presented with severe pruritus and jaundice at 16-17th week of her second pregnancy. The ICP was diagnosed after elevated total bile acids were detected. A medical pregnancy termination was induced with subsequent three sessions of plasmapheresis. The patient's condition deteriorated further before she received her second living, unrelated donor LT in December 2024.
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	2023.07.03- prior to pregnancy	2024.08.18- during the pregnancy	2024.09.30- A month after termination	2024.11.04	2025.02.02- Two months after re-transplantation
Total bilirubin (mg/dL) /norm 0-1.2/	1.5 N	17.6 H	20.2 H	40.6 H	0.73 N
GOT/GPT (IU/mL) /norm 0-40/	11.3/18.3 N	265.3/196.1 H	79.5/77.1 H	262.5/113.1 H	6.2/7.6 N
Total bile acids (umol/mL) /norm 0-10/		170.2 H	332 H		7 N

The explant histology stated a massive hepatocellular necrosis (fulminant), total bile duct loss, massive cholestasis (canalicular and intracellular), allograft arteriopathy: Foamy histiocytes in the intimal artery, Arteriosclerosis and Lumen narrowing. No genetic test was performed , either prior or after the LTs. The final diagnosis: An Intrahepatic Cholestasis of Pregnancy leading to a liver graft rejection.
The ICP is a relatively common pregnancy related condition (0.2-2% of pregnancies in Europe and Americas¹) that presents with jaundice and pruritus. The condition usually improves after delivery/termination. In rare cases elevated serum bile acid levels lead to fetal abnormalities or loss of pregnancy. Since the patients condition did not improve after the pregnancy termination in September, 2024, Progressive Familial Intrahepatic Cholestasis (PFIC) was suspected when she admitted her first pregnancy was also complicated by ICP. Better history taking is needed to prevent graft rejection due to bile acid transport dysfunction.

References

1- Williamson, C. and V. Geenes, Intrahepatic cholestasis of pregnancy. Obstet Gynecol, 2014. 124(1): p. 120-133

Clinical Case Summary

Aims: We report 3 cases of new inflammatory bowel disease (IBD) which occurred in multiple sclerosis (MS) patients undergoing ocrelizumab therapy over last year in Irish Teaching Hospital setting.
Background: Ocrelizumab, a monoclonal antibody targeting CD20-positive B cells, is an established treatment for MS. While it is generally well-tolerated, emerging reports suggest a possible link to gastrointestinal complications, including IBD.
Methods: Three MS patients presented after starting ocrelizumab with gastrointestinal symptoms suggestive of inflammatory bowel disease. They were fast-tracked for endoscopic evaluation by an experienced gastroenterologist specializing in IBD. Diagnosis was based on clinical presentation, endoscopic findings, and histological analysis. Data regarding symptom onset, disease severity, colitis grade, inflammation distribution, and treatment response were assessed.
Results: A temporal relationship was observed between ocrelizumab initiation and IBD onset in all three cases, with symptoms emerging after 4-6 infusions. Reported symptoms included diarrhoea, nausea, urgency, and abdominal pain. Faecal calprotectin levels at time of referral ranged from 900 to 1800 µg/g. Endoscopy confirmed mild colitis and terminal ileitis, while histology revealed active colitis with cryptitis, acute terminal ileitis, or normal colon findings. Treatment with steroids, Mesalazine, and antibiotics led to symptom resolution in all cases. Discontinuing ocrelizumab resulted in recovery within 4-6 weeks, with no relapse over an average follow-up of two months.
Conclusion: These cases suggest a potential association between ocrelizumab and IBD onset or exacerbation in MS patients. Symptom resolution upon drug withdrawal supports a possible causal relationship. Clinicians should be aware of this risk to facilitate early detection, management, and patient education.

References

https://journals.lww.com/acgcr/Fulltext/2022/01000/Severe_Ocrelizumab_Induced_Enterocolitis_Treated.31.aspx
https://pubmed.ncbi.nlm.nih.gov/32198886/

Disclosure

No Conflict of Interest

Introduction

In recent years, both the incidence and early-stage diagnosis of pancreatic neuroendocrine tumors (pNETs) have increased, likely due to advancements in cross-sectional imaging techniques (1). Management strategies are size-dependent, with observation generally preferred for lesions <10 mm and surgical resection for those >20 mm. However, there is no consensus regarding the optimal approach for tumors between 10 and 20 mm, highlighting the need for multidisciplinary decision-making (2). In this setting, endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) or fine-needle biopsy (FNB) plays a crucial role not only in diagnosis but also in tumor grading (3). However, samples obtained through EUS-FNA or FNB may not provide sufficient histological material to determine tumor grade in pNETs smaller than 20 mm. This study aims to summarize the current evidence regarding the adequacy of histological samples obtained via EUS-FNA/FNB for tumor grading.

Aims & Methods

This study followed the PRISMA guidelines for Systematic Reviews and Meta-Analyses. MEDLINE, EMBASE, and SCOPUS databases were searched up to December 2024 for studies reporting on the sample adequacy of EUS-FNA or FNB for grading pNETs ≤ 20 mm. Sample adequacy was defined as the proportion of samples in which the Ki-67 index was successfully obtained for tumor grading among all samples collected. Pooled estimates were calculated using random-effects models. Heterogeneity was assessed using the I² statistic. Subgroup analyses were conducted based on needle type (FNA vs. FNB).

Results

17 studies were included, analyzing a total of 1414 patients. The pooled adequacy rate was 71.6% (95% CI: 0.592–0.841), with substantial heterogeneity across studies (I² = 98.69%). The risk of publication bias was considered low based on Egger’s test (p = 0.162). When considering only studies that used FNA, adequacy rates were lower, with a pooled estimate of 52.5% (95% CI: 0.302–0.748; I² = 97.99%). In contrast, studies employing FNB showed higher adequacy rates, with a pooled estimate of 79.8% (95% CI: 0.605–0.991), although heterogeneity remained high (I² = 87.32%). In this subgroup, there was also evidence of publication bias, as suggested by Egger’s test (p = 0.017) and visual asymmetry in the funnel plot.

Conclusion

Our study found that EUS-FNA/FNB provides adequate histological specimens for tumor grading in pNETs < 20 mm, although significant heterogeneity was observed. As expected, FNB demonstrated considerably better performance than FNA in establishing tumor grade, suggesting it should be preferred for pNET sampling. However, even with FNB, tumor grade could not be determined in up to 20% of cases, indicating that it remains a suboptimal tool for grading and may offer limited additional value beyond diagnostic confirmation in some patients. Notably, our study did not distinguish between first-, second-, and third-generation FNB needles; therefore, results from newer-generation FNBs may show improved sample adequacy rates. Furthermore, the observed heterogeneity highlights the need for studies specifically evaluating the ability of EUS-FNB to obtain high-quality tissue for grading, thereby supporting the role of EUS in clinical decision-making for these small tumors.

References

1. Souche R, Hobeika C, Hain E, et al. Surgical Management of Neuroendocrine Tumours of the Pancreas. J Clin Med 2020;9.
2. Mansour JC, Chavin K, Morris-Stiff G, et al. Management of asymptomatic, well-differentiated PNETs: results of the Delphi consensus process of the Americas Hepato-Pancreato-Biliary Association. HPB (Oxford) 2019;21:515-523.
3. Franchellucci G, Andreozzi M, Carrara S, et al. Contrast Enhanced EUS for Predicting Solid Pancreatic Neuroendocrine Tumor Grade and Aggressiveness. Diagnostics (Basel) 2023;13.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) represents over 90% of pancreatic cancer cases and remains a highly lethal malignancy with a five-year survival rate below 12%. Although KRAS mutations drive approximately 90% of PDAC cases, the clinical efficacy of direct KRAS inhibitors remains limited, highlighting the critical need for alternative therapeutic targets. Kinases have emerged as promising candidates for PDAC treatment. Through a kinase-focused esiRNA library screen comparing KRAS-mutant and wild-type PDAC cell lines, we identified serine/threonine kinase 31 (STK31) as a KRAS-dependent oncogenic effector that promotes tumor progression by regulating key cell cycle proteins CCNB1 and CDC25C. However, STK31’s kinase activity, downstream signaling mechanisms, and pharmacologically targetable features remain unknown, representing a significant gap in our understanding of its therapeutic potential.

Aims & Methods

This study aims to characterize the molecular mechanisms of STK31’s kinase function and evaluate STK31 inhibitors for PDAC treatment using preclinical models. We employed 4D label-free phosphoproteomics to identify potential STK31 substrates, followed by in vitro kinase assays to validate phosphorylation activity. AlphaFold 3 was utilized for structure-based virtual screening of STK31 inhibitors.

Results

Our preliminary data demonstrate that STK31 exhibits intrinsic kinase activity and phosphorylates mTORC2, potentially regulating CCNB1 and CDC25C expression through STAT1 phosphorylation. AI-driven molecular docking identified ciclopirox as a putative STK31 inhibitor, which was subsequently validated in functional assays. Ciclopirox effectively suppressed PDAC cell growth, with enhanced potency in KRAS-mutant cell lines.

Conclusion

Based on these findings, we propose that STK31 drives PDAC progression via the mTORC2-STAT1-CCNB1/CDC25C axis and that pharmacological inhibition of STK31 represents a viable therapeutic strategy.

Introduction

Fatigue is highly prevalent in patients with Inflammatory bowel disease (IBD)and associated with reduced quality of life. However, effective treatments for IBD fatigue are lacking.

Aims & Methods

We aimed to assess the real-world efficacy of modafinil – a stimulant medication – on fatigue in IBD patients. The was a prospective evaluation in a tertiary IBD centre in the UK. Adults with a confirmed diagnosis of IBD, who were fatigued for at least 6 months, were referred for fatigue evaluation using the Inflammatory Bowel Disease Fatigue Self-Assessment Scale (IBD-F). The IBD-F includes 5 questions scored 0-4 using a Likert scale to identify fatigue. Scores range from 0-20 and scores ≥11 denote severe fatigue.
After treating organic causes of fatigue (anaemia, B12 deficiency, hypothyroidism, mucosal inflammation) and excluding contraindications, patients with a baseline IBD-F score ≥11 were offered modafinil. Modafinil was started at 100mg daily and titrated in 100mg increments to a maximum of 400mg daily if needed. If unable to tolerate 100mg, dosage was reduced to 50mg.
Patients were followed up until week 12 or drug withdrawal. IBD-F scores were reviewed at 12 weeks and compared to baseline. A clinically significant fatigue improvement was a reduction in the IBD-F score ≥3¹. Any patient who withdrew drug before 12 weeks was regarded as having severe fatigue at follow up.
Descriptive statistics were presented as means with standard deviation [SD]. A paired t-test was used to assess change in IBD-F scores from baseline with 5% significance level used.

Results

Seventy-two patients (50% male) were included with a mean age of 38 (SD 11.1) years . Of these, 53 (74%) had Crohn’s and 19 (27%) had UC with a mean disease duration of 13.2 (10.4) years (Table 1). The cohort showed refractory disease with 23 (32%) of patients having used at least 3 biologics, 24 (33%) had a stoma and 41(57%) had at least one bowel resection. The most common total modafinil dose was 200mg. Dosages ranged from 50mg to 400mg per day.
Both UC (15.9 [SD 2.58]) and Crohn’s (15.0 [2.31]) had similar mean (SD) baseline IBD-F scores. After treatment with modafinil, there was a statistically significant improvement in mean IBD-F score from baseline 15.3 [SD 2.38] to 10.4 [SD 3.83] (p<0.0001). There was no difference in the score improvement between UC and Crohn’s p=0.29. No difference was observed between those with and without irritable bowel syndrome (p=0.35). At follow up, 53 (74%) had a clinically significant improvement in fatigue and 38 (53%) were no longer severely fatigued.
Nine patients (13%) reported side effects: headache (n=5), and anxiety, mood changes, nausea, and visual issues (n=1 each). Three patients withdrew before the 12 week follow up. No serious adverse events were recorded.

Table1

Demographic Data	n =72 (%)
Male Female	36 (50) 36 (50)
Age:	mean 38 [SD 11.12] years
UC Crohn's	19 (26) 53 (74)
Disease Duration:	mean 13.2 [SD 10.39] years
Stoma	24 (33)
IBS	6 (8)
Smokers Ex smokers Non smokers	7 (15) 14 (31) 22 (49) n=45
No. of biologics used 0 1 2 3 4+	14 (19) 19 (26) 16 (22) 11(15) 12 (16)
Steroid use	25 (35)

Conclusion

In this real-world evaluation, modafinil was associated with a statistically significant improvement in fatigue in patients with mostly refractory IBD. Modafinil was generally well tolerated. Randomised, placebo-controlled trials of modafinil for IBD fatigue are now warranted.

References

1 Nocerino A, Nguyen A, Agrawal M, Mone A, Lakhani K, Swaminath A. Fatigue in Inflammatory Bowel Diseases: Etiologies and Management. Adv Ther. 2020;37(1):97-112. doi:10.1007/s12325-019-01151-w

Introduction

Chronic pancreatitis (CP) may have differences in causes, presentations and progression related to sex. There are few studies describing the sex related phenotype of CP.

Aims & Methods

We aimed to study sex differences in etiology, complications and treatment of CP in a large, North-European CP cohort. Data were extracted from the Scandinavian Baltic Pancreatic Club (SBPC) database. The collected data included sex, age, etiology, anthropometric measures, data for smoking and alcohol exposures and data on treatment and complications from CP. Differences between sexes were compared with multiple logistic regression models.

Results

We included 1922 patients in the analyses, of whom 1264 were men. Mean age of CP onset was 52.5 (SD 15.0) years in men and 51.5 (SD 16.4) years in women (p=0.2). In univariate analysis alcohol etiology and smoking was associated with male sex, whereas hereditary pancreatitis, efferent duct obstruction, autoimmune pancreatitis were associated to female sex. Numbers of men and women with non-alcoholic etiology were almost equal (461 and 422, respectively). In multivariate analysis including all etiologies, time with disease and age; alcohol etiology remained strongly associated to male sex (OR 2.92 (2.29-3.71), p<0.001), whereas duct obstruction etiology was associated with female sex (OR 0.62 (0.44-0.89), p=0.01).
Significantly more women were underweight (p<0.001), and more men were overweight (p<0.001). Concerning other complications, diabetes mellitus (DM) was strongly associated with men (OR 1.62 (1.27-2.07), p<0.001), whereas osteoporosis was strongly associated with women (OR 0.47 (0.32-0.70), p<0.001). Recurrent acute pancreatitis and exocrine insufficiency were equally distributed between the sexes. There were no differences between sexes for medical, endoscopic or surgical treatment options.

Conclusion

More men than women had alcohol induced CP, but there was almost no difference in absolute numbers of men and women with non-alcoholic CP. Among the CP patients, DM was associated with men, while osteoporosis was associated with women.