Introduction

Capsule endoscopy is the first-line examination for digestive bleeding with likely origin in the small bowel, in hemodynamically stable patients. In the 2022 update, ESGE guidelines recommend that, in the context of overt bleeding, capsule enteroscopy should be performed as soon as possible, ideally within the first 48 hours. In the previous guidelines, published in 2015, the recommended window was 14 days.

Aims & Methods

This study aimed to evaluate the improvement in yield offered by the new recommendations regarding the timing of urgent capsule enteroscopy. Patients with suspected overt middle gastrointestinal bleeding between January 2005 and November 2022 were retrospectively analyzed. Diagnostic and therapeutic yield, rebleeding rate, and mortality were compared when capsule enteroscopy was performed within the first 48 hours, within the first 14 days, or between the 3rd and 14th day after admission.

Results

A total of 138 patients were included (58.7% men, median age 66 years), 87 of whom (63.0%) underwent capsule enteroscopy within the first 48 hours after hospital admission. The median follow-up was 55 months (5-180). The diagnostic yield (presence of blood or lesions with bleeding potential) was slightly higher when capsule enteroscopy was performed within the first 48 hours (81.6% versus 76.5%, p=0.349). On the other hand, capsule enteroscopy within the first 48 hours was significantly associated with higher therapeutic yield (endoscopic, radiologic, or surgical treatment) - 54.0% versus 39.2%, p=0.02. The rebleeding rate was significantly lower in patients undergoing enteroscopy within 48 hours after admission (19.5% versus 29.4%, p=0.04). On the other hand, overall mortality at 36 months did not differ between strategies (21.8% and 25.5%, p=0.401).

Conclusion

Performing capsule endoscopy within the first 48 hours, as recommended by recently published guidelines, is associated with favourable short- and long-term clinical outcomes.

Introduction

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, predominantly diagnosed in patients with chronic liver diseases. The absence of specific biomarkers and the typically asymptomatic progression of the disease lead to delayed diagnosis. Patients with liver disease, including HCC, exhibit alterations in the gut microbiome and increased bacterial permeability, factors that may influence disease progression and patient outcomes. In recent years, there has been a growing interest in exploring circulating microbiome signatures as potential indicators of liver disease stutus, providing a new avenue for understanding HCC.

Aims & Methods

Aims: To identify the signatures of the circulating blood microbiome associated with hepatocellular carcinoma, response to treatment and disease prognosis.
Methods: This study conducted a post-hoc analysis of the SORAMIC clinical trial utilizing peripheral blood plasma samples. For this analysis, blood plasma samples from a cohort of 71 patients with HCC were examined (25 treated with Sorafenib and 46 with SIRT/Sorafenib). Peripheral blood samples were collected at two time points: baseline (prior to the initiation of anti-tumor therapy) with all 71 patients included, and post-therapy (7 to 9 weeks after treatment) with 39 patients included. Additionally, peripheral blood samples were obtained from 52 control subjects, who were endoscopically diagnosed with colonic diverticulosis, to compare against the patient group. The composition of the circulating blood microbiome was assessed through 16S rRNA gene sequencing, targeting the V1-V2 hypervariable regions. Subsequent analyses focused on identifying associations with potential novel biomarkers for diagnosis, prognosis, and response to treatment.

Results

Patients with HCC had significantly diminished α-diversity of the circulating blood microbiome as compared to controls. Significant differences were also observed in between microbial communities of these two cohorts based on Bray-Curtis dissimilarity index. Patients with HCC had significantly higher levels of Proteobacteria and Bacteroidetes and lower levels of Firmicutes and Campylobacterota. Differential abundance analysis revealed that families of Gordoniaceae, Cryomorphaceae, Burkholderiaceae, Comamonadaceae, Enterobacteriaceae were significantly enriched in patients with HCC. At the genus level, patients with HCC had higher levels of Gordonia, Fluviicola, Burholderia, Limnohabitans and Escherichia/Shigella and lower levels of Corynebacterium. HCC patients, who responded to treatment with SIRT/Sorafenib showed an increase in blood bacterial diversity, enrichment of families Burkholderiales incertae sedis, Arcobacteraceae, Peptostreptococcaceae, Moraxellaceae, genera Sphaerotilus, Aliacrobacter, Rhodoluna, Giesbergeria, Microbacterium, Romboutsia, Arcicella, Pseudorhodoferax and depletion in families Gordoniaceae, Cryomorphaceae and genera Cloacibacterium, Gordonia, Limnohabitans, Fluviicola after the treatment. Levels of Acinetobacter, Enhydrobacter and Micrococcus in the blood before the HCC treatment were associated with patient prognosis.

Conclusion

Patients with HCC exhibit a unique circulating blood microbiome profile characterized by reduced bacterial diversity. Response to treatment is linked to an increase in α-diversity and changes in the circulating microbiome profile. Specific members of the circulating microbiome show potential prognostic capabilities, suggesting their utility as biomarkers for predicting disease progression and treatment outcomes in HCC.

Clinical Case Summary

A 40-year-old male came to our emergency department referring worsening jaundice, mental status deterioration, epigastric pain and anorexia over the past week. Four weeks earlier he presented odynophagia, myalgias, and hand pruritus but didn’t seek medical attention.
Patient’s clinical background included cognitive impairment due to peripartum anoxia and type 2 Diabetes Mellitus. At admission, he had elevated liver enzymes (R value=2,7), coagulopathy (INR 1.3), pancreatic enzymes >3 times the upper normal level and hyperbilirubinemia (mostly conjugated).
The CT-scan revealed pancreatic tail globosity, diffuse abdominal and retroperitoneal peri-centimetric lymph nodes and excluded biliary lithiasis.
After common causes of acute hepatitis and pancreatitis were ruled out, and since patient was at risk of acute liver failure despite supportive treatment, a liver biopsy was performed. Autoimmune hepatitis, drug-induced liver injury or lymphoproliferative disease were held as potential differentials. Hepatitis E Virus (HEV) RNA was then found and genotyped in the serum (genotype 3). HEV infection was assumed as the cause for both hepatitis and pancreatitis. Histological pattern was inconclusive and epidemiological source wasn’t found.

HEV infection paradigm has changed and is now considered an endemic zoonotic infection in most high-income countries (Portuguese seroprevalence is 16.3%)¹. Infection occurs due to ingestion of undercooked pig or boar meat and should be suspected in every acute hepatitis, mostly with a cholestatic pattern.
The setting of acute HEV hepatitis complicated with acute pancreatitis (AP) is uncommon². AP usually starts after a median of 10 days of jaundice onset³. Literature only reports association between AP and HEV caused by genotype 1 from Southeast Asia^{3 4}, and genotype 3 was only related to gallstone-related pancreatitis, according to current knowledge⁵. This might be the first form of HEV genotype 3 infection with hepatitis and pancreatitis.

References

1. Nascimento MSJ, Pereira SS, Teixeira J, et al. A nationwide serosurvey of hepatitis E virus antibodies in the general population of Portugal. Eur J Public Health 2018;28(4):720-24. doi: 10.1093/eurpub/ckx213 [published Online First: 2017/12/14]
2. Debnath P, Datta AK, Chakraborty U, et al. Acute viral hepatitis E complicated with acute pancreatitis in an immunocompetent adult. BMJ Case Rep 2021;14(2) doi: 10.1136/bcr-2020-239684 [published Online First: 2021/02/06]
3. Haffar S, Bazerbachi F, Garg S, et al. Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review. Pancreatology 2015;15(4):321-6. doi: 10.1016/j.pan.2015.05.460 [published Online First: 2015/06/08]
4. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018;68(6):1256-71. doi: 10.1016/j.jhep.2018.03.005 [published Online First: 2018/04/04]
5. Karlsson M, Norder H, Bergstrom M, et al. Hepatitis E virus genotype 3 is associated with gallstone-related disease. Scand J Gastroenterol 2019;54(10):1269-73. doi: 10.1080/00365521.2019.1666163 [published Online First: 20190925]

Clinical Case Summary

A 62 y/o male complaining from epigastric pain, constipation, vomiting and eructation for two months and CT abd revealed irresectable pancreatic head mass 4.5x4.5 cm encasing PV and SMV with duodenal invasion. Ryle decompression was done before EGD, duodenal obstruction was noted and biopsy showed duodenitis (stasis induced). EUS-FNB confirmed well differentiated AC. Duodenal stenting was successfully performed with improving symptoms.
After one week patient complained from weakness and abnormal gait, examination showed normal vital signs, bilateral lower limb edema and patient was lethargic. Three days after, the patient became confused (GCS 12), so he was admitted to ICU.
CT brain was unremarkable. Lab investigations showed the following:
Na 130, K 4.1, Ca 7.8, Phos 2.8, Mg 2.6, Alb 2.9
Refeeding injury was suspected and TPN was started by the ICU team. No improvement of the consciousness was achieved and patient caught chest infection, developed sepsis and died.
Discussion: Refeeding syndrome is a serious complication that can be easily missed [1] in upper GI malignant obstructions with prolonged decreased oral intake along with the malignancy cachexia status. These obstructions may need surgery or stenting to regain patency and without cautious monitoring of the nutrients repletion rate either enteral or parenteral this will lead to fluid and electrolyte disturbance (Fluid balance abnormalities, Abnormal glucose metabolism, Vitamin deficiency, e.g., vitamin B1 (thiamine), Hypophosphatemia, Hypomagnesaemia and/or Hypokalemia) [2] with symptoms ranging from vague up to life threatening conditions like disturbed conscious level and heart failure. Our patient had high risk of developing refeeding syndrome due to caloric deprivation secondary to duodenal obstruction with development of the symptoms after stenting and restarting oral intake.
Conclusion: Nutritionist counseling after GI stenting of upper GI malignant obstructions is needed to avoid refeeding syndrome.

References

[1] Reber, E., Friedli, N., Vasiloglou, M.F., Schuetz, P. and Stanga, Z., 2019. Management of refeeding syndrome in medical inpatients. Journal of clinical medicine, 8(12), p.2202.
[2] Crook, M.A., Hally, V. and Panteli, J.V., 2001. The importance of the refeeding syndrome. Nutrition, 17(7-8), pp.632-637.

Introduction

Ustekinumab, an interleukin (IL) 12/23 inhibitor is a biologic used to treat inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Clinical and real-world evidence has demonstrated its ability to provide a clinically meaningful response and remission among patients; however, the economic impact of its use may not be favourable from the payer perspective. The objective of this targeted literature review was to understand the economic impact of ustekinumab reference product in the treatment of patients with IBD.

Aims & Methods

A literature search was conducted in MEDLINE for economic publications that evaluate the economic impact of ustekinumab or include ustekinumab within their analyses. Search terms included “budget impact model”, “budget impact analysis”, “cost-utility”, “cost-effect”, “ulcerative colitis”, “Crohn’s disease” and “ustekinumab” from database inception until Feb 8^th, 2024. Only studies published in English were eligible for inclusion.

Results

A total of 30 hits were screened for inclusion, yielding 12 relevant studies that discussed economic implications of ustekinumab. Five articles were conducted from the US payer perspective, two from the Japanese payer perspective, and one each from the Canadian, Swedish, Polish, French, and German perspectives. The economic models included budget impact models (n = 2), cost-effectiveness models (n = 8), and cost per responder/remitter analyses (n = 2). Five studies used a CD patient population, six studies focused on UC, and one study included a mixed population of CD and UC. In CD studies, two found ustekinumab was cost-effective: these studies were conducted from the perspective of Polish and Swedish payers in CD patients who failed anti-TNF therapy. Both studies used a Markov based model to assess cost-effectiveness of treatments. In the remaining CD studies, ustekinumab was associated with the highest cost per responder/remitter (Japanese payer perspective) and was dominated by other treatments in cost-effectiveness analyses (US payer perspective). The studies conducted in the UC patient population also found that, although clinically effective, ustekinumab was dominated (based on the incremental cost effectiveness ratio [ICER]) by other biologics included in the analyses (eg, vedolizumab and infliximab). Similar to the CD patient population, the cost per responder/remitter was highest for ustekinumab compared to five other therapies including tofacitinib and golimumab (US payer perspective). However, in two UC studies, ustekinumab was observed to be more effective than the most cost-effective treatment option (from the Japanese and US payer perspectives), highlighting that its price negatively affected its ICER. Moreover, cost-effectiveness analyses conducted by the German and Canadian perspectives, demonstrated that ustekinumab was not a cost-effective therapy at the current willingness to pay threshold (0% probability). Note, that no studies tested the possible cost-effectiveness of an ustekinumab biosimilar which would positively influence the cost associated with ustekinumab treatment.

Conclusion

This literature review demonstrated that, despite its high efficacy, ustekinumab is among the highest costing biologics available for the treatment of IBD with low probabilities of cost-effectiveness across several studies. As the economic burden for IBD is increasing globally, cost-saving therapeutic options such as biosimilars may help to provide savings that can be redistributed in a healthcare system or provide funds to expand patient access.

Disclosure

Kunal Shastri is an employee of Fresenius Kabi a manufacturer of biosimilars. Kerise Clarke, Margaret Ainslie-Garcia, Nicole Ferko are employees of EVERSANA a company who receives consulting fees from Fresenius Kabi.