Clinical Case Summary

A 21-year-old female patient from a remote village in East Africa presented multiple times to a small local hospital near her village with recurrent severe rectal bleeding. Each time she was offered blood transfusion and supportive care for possible dysentery. As the frequency of her bleeding increased, she was transferred to a district general hospital, where she underwent a flexible sigmoidoscopy after administration of a rectal enema. The distal colonic mucosa was reported to appear quite dark without active bleeding at the time. A couple of mucosal biopsies were taken, and the histology was reported to show non-specific mucosal inflammation. Few hours after the biopsy, the patient developed massive rectal bleeding and went into a shock. Her haemagolobin went down to 2.2 g/dl. She was successfully resuscitated, and a few days later was referred to our GI specialist hospital. After a full oral bowel preparation, the patient underwent a full colonoscopy, which showed multiple tortuous veins covering the whole rectum and continuing to distal descending colon, consistent with extensive left-sided colonic varices (Figures 1-3). At the time of colonoscopy, there was no active bleeding.
The patient was screened for chronic liver disease with laboratory tests, ultrasound abdomen and pelvis as well as an upper GI endoscopy, which were all normal. She also underwent a CT mesenteric angiogram, which was also normal. We discussed left hemicolectomy for her but the patient declined, and we offered her empirical non-selective beta blocker (propranolol), and she returned to her village. At follow up at six and 12 months, she reported only one episode of self-limiting rectal bleeding. She continues with the beta blockers and remains stable and in good health.

References

Figure 1: Colonic varices in rectum.
Figure 2: Colonic varices in sigmoid and descending colon.
Figure 3: Lower oesophagus- No evidence of varices.

Introduction

People who use drugs (PWUD) are an important target population for hepatitis C virus (HCV) elimination in the World Health Organization (WHO) goals, because the PWUD population contains one of the largest clusters of residual HCV infections. Case-finding and treatment of these patients in hospitals is considered a challenge, while low threshold on-site screening and therapy in addiction care might facilitate viral elimination. We studied implementation of a decentralized PWUD-HCV care model, by exploring 1) viral elimination rates, and 2) facilitators and barriers for implementation.

Aims & Methods

In a multicenter mixed-method study in addiction care centers in the Netherlands we examined HCV-related outcomes in PWUD receiving HCV treatment within addiction care. The primary outcome was viral elimination, defined as percentage of identified HCV positive patients achieving sustained virologic response (SVR). Using semi-structured interviews barriers and facilitators for implementation were identified among health professionals and policy makers of addiction care and hospitals.

Results

We found 33 PWUD HCV RNA positive. Four patients were referred to the hospital for treatment due to hepatitis B virus or HIV co-infection or other reasons. Two patients currently receive treatment, three patients were not yet fit for treatment and two were lost to follow-up before treatment could be started. On-site treatment was initiated in 22 patients. Of these patients 91% was male, mean age was 50 years (SD=13) and 36% was born in the Netherlands. All patients completed treatment with glecaprevir/pibrentasvir (n=9) or sofosbuvir/velpatasvir (n=13). All on-site and hospital treated patients reached SVR and there were no reinfections. The viral elimination rate was 79% (26/33). Themes on facilitators and barriers for implementation collected in the interviews are shown in the table.

Conclusion

This study shows the high viral elimination (79%) of decentralized care of HCV infections within addiction care and provides insight in facilitators and barriers for on-site HCV treatment. Based on these findings we recommend implementation and maintenance of decentralized HCV-addiction care models worldwide. This will lead to HCV elimination scaling-up in the Netherlands and abroad, furthering WHO goals.

References

Madden, A., Hopwood, M., Neale, J., & Treloar, C. (2018). Beyond interferon side effects: What residual barriers exist to DAA hepatitis C treatment for people who inject drugs? PLoS One, 13(11), e0207226. https://doi.org/10.1371/journal.pone.0207226
Oru, E., Trickey, A., Shirali, R., Kanters, S., & Easterbrook, P. (2021). Decentralisation, integration, and task-shifting in hepatitis C virus infection testing and treatment: a global systematic review and meta-analysis. The Lancet Global Health, 9(4), e431-e445. https://doi.org/10.1016/s2214-109x(20)30505-2
Von den Hoff, D. W., Berden, F. A. C., Atsma, F., Schellekens, A. F. A., & Drenth, J. P. H. (2022). Against All Odds? Addiction History Associated with Better Viral Hepatitis Care: A Dutch Nationwide Claims Data Study. J Clin Med, 11(4). https://doi.org/10.3390/jcm11041146
European Association for the Study of the Liver, e. e. e., Clinical Practice Guidelines Panel, C., representative, E. G. B., & Panel, m. (2020). EASL recommendations on treatment of hepatitis C: Final update of the series(). J Hepatol, 73(5), 1170-1218. https://doi.org/10.1016/j.jhep.2020.08.018

Disclosure

Daan Von den Hoff and Joost Drenth declare receipt of funds from Abbvie and Gilead; the other authors have nothing to declare.

Introduction

Chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in hematological malignancies, but remain largely ineffective in solid tumors such as pancreatic ductal adenocarcinoma (PDAC). Major barriers include CAR-T cell dysfunction, poor infiltration, and limited persistence within the immunosuppressive tumor microenvironment. STING (stimulator of interferon genes) activation can remodel this environment by inducing inflammation and reversing cancer immune privilege. However, the use of STING agonists in combination with CAR-T cells is hampered by T cell-intrinsic STING signaling, which induces T cell dysfunction and apoptosis.

Aims & Methods

To overcome these limitations, we investigated the therapeutic potential of combining STING agonists with CAR-T cells genetically ablated for STING for the treatment of PDAC. Using CRISPR-Cas9-edited CAR-T cells and the STING agonist diABZI, we assessed antitumor activity in vitro using a CAR-T cell exhaustion model and in vivo using both a cell line-derived xenograft and a syngeneic mouse model.

Results

The combination of STING^KO CAR-T cells and diABZI substantially enhanced CAR-T cell function. In vitro, we observed improved tumor cell killing, increased CAR-T cell proliferation, reduced expression of exhaustion markers, and expansion of an effector-memory phenotype. These effects required genetic deletion of STING in CAR-T cells and were dependent on cancer cell-intrinsic STING signaling. Mechanistically, we identified a synergistic feedback loop, in which CAR-T cell-derived IFN-γ and TNF-α enhanced STING signaling in cancer cells, further promoting beneficial CAR-T cell states. In vivo, this combination achieved superior tumor control in both xenograft and syngeneic mouse models.

Conclusion

Our findings demonstrate that STING^KO CAR-T cells can be effectively combined with STING agonists to enhance therapeutic efficacy in immune-cold tumors such as PDAC. This strategy represents a promising approach to overcoming current barriers in CAR-T cell therapy for solid tumors.

Disclosure

I.P. reports reimbursement of travel expenses from Roche and received third-party funding for scientific research from Novartis. A.G. received research support from Tabby Therapeutics and from Nanogami for work unrelated to the paper. M.S. has received research funding from Amgen, BMS/Celgene, Gilead/Kite, Janssen, Miltenyi Biotech, Molecular Partners, Novartis, Roche, Seagen and Takeda, honoraria from AbbVie, Amgen, AvenCell, BMS, CanCell Therapeutics, Gilead, Janssen, Miltenyi Biomedicine, Molecular Partners, Pfizer and Roche and was invited as speaker by AstraZeneca, BMS, Gilead/Kite, GSK, Janssen, LAWG, Novartis, Pfizer, Roche and Springer Healthcare. S. K. has received honoraria from Cymab, Plectonic, TCR2 Inc., Miltenyi, Galapagos, Novartis, BMS and GSK. S. K. is an inventor of several patents in the field of immuno-oncology. S. K. received license fees from TCR2 Inc and Carina Biotech. S.K. received research support from TCR2 Inc., Tabby Therapeutics, Catalym GmBH, Plectonic GmBH and Arcus Bioscience for work unrelated to the manuscript. The other authors have no competing interests to declare.

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is a frequently employed procedure for diagnosing and treating pancreaticobiliary diseases. The selection of an appropriate sedative agent is crucial for ensuring patient comfort and procedural success. An optimal sedative should offer a predictable duration of action and a high safety profile. This study aimed to compare the efficacy and safety of remimazolam and propofol in patients undergoing ERCP procedures.

Aims & Methods

A randomized, single-blind, single center study was conducted comparing remimazolam and propofol for inpatient ERCP sedation. The study medications were administered under the supervision of the endoscopist. A total of 110 patients scheduled for ERCP were randomly assigned to receive either remimazolam or propofol. The primary endpoint was a composite of successful procedure completion and no requirement for rescue medication. Secondary endpoints included sedation efficacy, recovery time, and adverse events.

Results

Of the 110 patients randomized, 108 underwent sedation and ERCP (53 received remimazolam, 55 propofol). The primary endpoint was achieved for 100% of patients in both groups. The incidence and frequency of treatment-emergent adverse events, including desaturation, were comparable between the two groups. ERCP initiation occurred sooner in the propofol group (mean, 63.18 ± 16.56 seconds) compared to the remimazolam group (75.23 ± 32.27 seconds; p-value=0.02). Additionally, the time to full alertness after ERCP completion was significantly shorter in the propofol group than the remimazolam group (304.18 ± 146.25 vs. 448.34 ± 224.09 seconds; p-value<0.001).

Conclusion

This trial demonstrated non-inferiority of remimazolam to propofol in achieving the primary endpoint of successful ERCP completion without the need for rescue medication. The incidence and frequency of adverse events were comparable between the two groups. However, our study also revealed that propofol had a faster onset and recovery time compared to remimazolam. Although this difference may not be clinically significant, it could have practical implications in certain cases. Consequently, remimazolam can be considered a safe and effective alternative to propofol for ERCP sedation, potentially expanding clinicians’ options and improving patient outcomes. Further research is warranted to determine the optimal choice of sedative agents for various patient populations and procedures.

Introduction

Ulcerative colitis (UC) has increasingly been recognized as a progressive disease. However, the benefit of starting early biologic therapy (BT) has not been established, contrary to Crohn´s disease. We aimed to assess if early intervention improves UC outcomes, particularly in preventing disease progression.

Aims & Methods

We conducted a retrospective multicenter study (11 centers) including adult UC patients who initiated BT until 2019 (minimum follow-up [FU]: 5 years). Early intervention was defined as BT initiation within ≤12 months of diagnosis. The primary outcome was UC progression at 5 and 10 years, defined as a composite of proximal extension, colonic structural changes (stenosis/ tubularization) and dysplasia/cancer. Secondary outcomes included clinical endpoints: hospitalizations, colectomy and corticosteroid use. Multivariate analysis was performed, adjusted for disease severity, extent, and prior activity.

Results

A total of 236 patients were included, with 28.8% (n=68) initiating BT within ≤12 months (mean FU after BT initiation: 8.06 ± 4.12 years).
Early intervention was associated with a reduced risk of proximal extension after BT initiation (p=0.012). In multivariable Cox regression, later BT initiation was an independent predictor of colonic structural changes at 10 years (HR 8.54; 95% CI 1.15-62.63; p=0.036). Later BT initiation independently predicted the composite outcome of progression (23.2% vs 5.9%) at 5 years (HR 5.97; 95% CI 1.42-25.13; p=0.015) and 10 years (HR 4.58; 95% CI 1.41-14.88; p=0.011). No differences in clinical outcomes were observed.
Longer disease activity before BT was also a predictor of the primary outcome at 5 years (HR 4.20; 95% CI 1.27–13.82; p=0.018) and 10 years (HR 3.60; 95% CI 1.28–10.12; p=0.015).

Conclusion

Starting BT early in the disease course may reduce the long-term risk of disease progression, reshaping the window of opportunity in UC.

References

Lujan, Rona, et al. "Early initiation of biologics and disease outcomes in adults and children with inflammatory bowel diseases: results from the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort." Gastroenterology 166.5 (2024): 815-825.

Introduction

Currently, about 25-30% of the world population is affected by non-alcoholic fatty liver disease (NAFLD); over time, about 20% tends to develop a certain degree of inflammation in the liver tissue, defying the non-alcoholic steatohepatitis (NASH). Moreover, approximately 20% of NASH patients evolve into a high-grade liver fibrosis condition that leads to severe liver impairment (cirrhosis) (1, 2, 3).
The serial use of non-invasive fibrosis tests can refine prognosis in patients with non-alcoholic fatty liver disease (NAFLD) and evaluate the progression or improvement of liver fibrosis.

Aims & Methods

We evaluated predictors of improvement or worsening of liver stiffness measurements (LSM) in well characterized cohorts of patients with NAFLD from London (UK) and Milan (Italy).
We included two consecutive cohorts of 405 patients with at least two outpatient visits between 2014 and 2022. The minimum time interval between baseline and follow-up LSM was >6 months. LSM worsening was defined as an increase of >20% kPa if the baseline LSM was ≥5 kPa, or a follow-up LSM >6 kPa if the baseline LSM was <5 kPa. An LSM improvement was defined as an LSM decrease of >20% kPa (if the baseline LSM was >6 kPa).
A significant change in weight was defined as a >5% reduction or increase at follow-up, while a significant change in glycated hemoglobin (HbA1c) was defined as a >10% reduction or increase.
The variation between the true and expected FIB-4 index (based on the patient’s age at the follow-up visit, but using the blood tests performed at the first visit) was calculated. A significant improvement or worsening in FIB-4 was defined as a >20% variation between the actual and “expected” FIB-4.

Results

Of the 405 patients, 282 (70%) were males; mean age was 54±11 years. The median time from the first visits was 20.3 (13.9 – 28.7) months.
128 and 54 patients had an LSM >8 kPa and LSM>12 KPa at follow-up, respectively.
77 patients (19.3%) had an LSM improvement, while 67 (16.8%) had an LSM worsening; 256 patients (63.9%) maintained a stable value.
In patients with an LSM improvement, 22 had an improvement, 12 had worsening, while 37 had stable FIB-4.
In patients with an LSM worsening, 10 had an improvement, 20 had worsening, while 33 had a stable FIB-4.
In multiple logistic regression analysis, LSM worsening was independently associated with an increase in ALT and in HbA1c levels (OR 1.02 and 1.03 respectively), but also with a reduction in total cholesterol and AST levels (OR 0.98 for both). LSM improvement was independently associated with weight and ALT reduction (OR 0.93 and 0.98 respectively), but also with an increased AST level (OR 1.02).

Conclusion

More than 35% of patients with NAFLD have significant changes in their LSM measurements over a period of 20 months, with worsening or improvement at similar rates. Improvement in weight is independently associated with significant improvement in LSM measurements. On the converse, worsening in metabolic comorbidities, particularly glycemic control, could be associated with significant worsening in LSM, further supporting a multidisciplinary model of care.

References

1. Younossi Z, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15(1):11-20.
2. Sheka AC, et al. Nonalcoholic Steatohepatitis: A Review. JAMA 2020;323(12):1175-1183.
3. Liu J, et al. Estimating global prevalence, incidence, and outcomes of non-alcoholic fatty liver disease from 2000 to 2021: systematic review and meta-analysis. Chin Med J (Engl). 2022 Jul 20;135(14):1682-1691.