Introduction

Piecemeal endoscopic mucosal resection (EMR) vs endoscopic submucosal dissection (ESD) has been a long standing debate in the endoscopic community worldwide with multiple studies done to evaluate the preferred method to manage large colorectal neoplasms. Piecemeal EMR with thermal ablation of the margin has been strongly advocated and reported by certain groups to be a simple, inexpensive and effective technique and this has been preferred widely due to its perceived ease of performance and shorter learning curve.¹ However, close, repeated surveillance colonoscopy is recommended even when the lesion is thought to have been completely resected² as residual tumors can cause interval cancers.³ Some groups, mainly from east Asian countries, have recommended en bloc resection by ESD due to significantly lower risk of local recurrence and precise pathological diagnosis.⁴ But its usage is limited due to concerns about risk of serious adverse events. With improvement in training and devices, colorectal ESD is now being performed by various centers globally. This study aims to report the outcomes of an international, multicenter study on colorectal ESD.

Aims & Methods

Patients who underwent colorectal ESD for lesions greater than 20mm between January 2022 to April 2024 from centers in USA, Japan, and India respectively were included in this study. Recurrent lesions after endoscopic therapy, neoplasms identified in patients with ulcerative colitis, and non-epithelial lesions were included. Primary outcomes were en bloc and R0 resection rate, delayed adverse events (bleeding/perforation), and local recurrence rate. Secondary outcomes were procedure time, lesion size, and pathology. Univariate and multivariate analysis were done to identify the risk factors for primary outcomes.

Results

309 patients (median size, 40(27.5-60)mm; location rectum 52.4%, left colon 26.2%, right colon 21.4%) were involved in this study. The en bloc resection rate was 96.1% and R0 resection rate was 90.3%. 3 patients experienced delayed bleeding which was managed endoscopically. 2 patients underwent surgery for delayed perforation. 6 patients had a local recurrence. 67(23%) patients had intramucosal carcinoma on pathology. Univariate analysis showed lesser procedure time (median(IQR) 145(80-236.25) vs 270(180-300) minutes, P= 0.005) and smaller lesion size (median(IQR) 40(26-56.25) vs 60(40-90) mm, P= 0.004) were significant factors for successful en bloc resection. However, lesser procedure time (median(IQR) 74(29.5-97.5) vs 150(82.5-240) minutes, P= 0.034) led to an increased delayed adverse event rate. Multivariate analysis using Cox regression showed en bloc resection (odds ratio 0.038; 95% confidence interval 0.003-0.421; P= 0.008) was an independent factor preventing local recurrence.

Conclusion

This international, multicenter study with data from three countries shows favorable outcomes for colorectal ESD for large lesions. The high en bloc and R0 resection rate, and low adverse event rate show increased global adaptation to this procedure. Reduced local recurrence is an added benefit. Data from a more centers globally will be valuable to establish ESD as the standard for large colorectal neoplasms.

References

1. Sidhu M, Shahidi N, Gupta S et al. Outcomes of thermal ablation of the mucosal defect margin after endoscopic mucosal resection: a prospective, international, multicenter trial of 1000 large nonpedunculated colorectal polyps. Gastroenterology. 2021 Jul 1;161(1):163-70.
2. Gupta S, Lieberman D, Anderson JC et al. Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2020;91:463-485.e5.
3. Rutter MD, Beintaris I, Valori R et al. World Endoscopy Organization Consensus Statements on Post-Colonoscopy and Post-Imaging Colorectal Cancer. Gastroenterology 2018;155:909-925.e3.
4. Ohata K, Kobayashi N, Sakai E et al. Long-term outcomes after endoscopic submucosal dissection for large colorectal epithelial neoplasms: a prospective, multicenter, cohort trial from Japan. Gastroenterology. 2022 Nov 1;163(5):1423-34.

Clinical Case Summary

Colorectal lymphomas are a rare cause of colonic neoplasia (0.2-0.6% malignant neoplasms of large bowel). Approximately 10% are primary colorectal lymphomas, while the rest correspond to colonic extension of systemic lymphoproliferative diseases.
We present the case of a 66-year-old woman with a history of rectum and pancreas adenocarcinoma (both in remission). During a follow-up CT, a thickening of the cecal pole was identified, with no adenopathy or other relevant findings (Photo1). The patient had no abdominal pain or B symptoms (night sweats, weight loss or fever).
The diagnosis was completed with a PET-CT that showed pathological uptake in the cecum (Photo2), so a colonoscopy was performed, which revealed a large polypoid lesion (30 mm) at the ileocecal level, with nodular areas with small ulcerations and no clear loss of the glandular pattern (Photo 3), from which multiple biopsies were taken.
Biopsies showed lymphoid proliferation with a ‘starry sky’ pattern, mitosis and apoptosis, and positive immunohistochemistry for CD45, CD20, CD10, BCL6, BCL2 and C-MYC, together with a high proliferation index (Ki-67 > 95%), all compatible with high-grade B-lymphoproliferative syndrome with Burkitt morphology (Photo 4).
Burkitt's lymphoma is a rare B-cell lymphoma (15% of GI lymphomas), associated with chromosomal translocation (8:14, 8:22 and 2:8) and overexpression of c-myc oncogene.
There are three clinical variants: endemic (common in Africa and associated with EBV and malaria), HIV-associated and sporadic (20%).
It is common in children and its most frequent symptoms are abdominal pain and weight loss, so diagnosis is often delayed. Although the yield of endoscopic biopsies is low (<20%), it is a key tool in its diagnosis, along with targeted biopsy of abdominal adenopathies.
Despite its aggressiveness, treatment with targeted chemotherapy achieves rates of more than 90%, and early diagnosis is essential to avoid complications and ensure adequate medical treatment.

References

- Photo 1: Thickening of the cecal pole seen in CT-Scan.
- Photo 2: Pathological uptake in the caecal area as seen on PET-CT Scan.
- Photo 3: Polypoid lesion in ileocecal area at colonoscopy
- Photo 4: Pathological anatomy of endoscopic biopsies: starry sky imaging and immunohistochemistry of Bcl-2 and C-myc

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 submucosal dissection (ESD) is a valuable technique for the en-bloc resection of superficial neoplasms in the anal canal. However, its safety and efficacy in patients who have previously undergone transanal endoscopic surgery (TES) —such as transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery (TEM)—remain unclear.

Aims & Methods

To assess the safety and outcomes of ESD in the anal canal for patients with a history of TES compared to naïve patients.
A retrospective analysis was conducted at our tertiary center on 51 patients who underwent ESD in the anal canal between March 2010 and November 2024. Patients with a history of transanal endoscopic surgery were compared to those undergoing ESD as their primary treatment. Key parameters, including resection speed, perforation rates, coagrasper usage, inpatient status, late hemorrhage, and recurrence, were evaluated. Statistical analysis was performed to determine significant differences between groups.

Results

Histological examination confirmed the following cases: 3 adenocarcinomas (including 1 non-curative ESD), 15 adenomas with high-grade dysplasia, 11 adenomas with low-grade dysplasia, 2 sessile serrated lesions, 15 sessile serrated lesions with dysplasia, 2 high-grade intraepithelial lesions, 2 low-grade intraepithelial lesions.
The median resection velocity was slightly lower in patients with recurrence (16.01 mm²/min) compared to those without recurrence (25.56 mm²/min), though this difference did not reach statistical significance (p = 0.062). Perforation occurred in 9.62% of cases, with similar rates between groups (p = 0.58), suggesting that prior TEM does not significantly increase the risk of this complication. Late hemorrhage was observed in 7.84% of patients, again without a significant difference between groups (p = 0.29).
The only statistically significant finding was the smaller lesion size in patients with recurrence (1,162 mm² vs. 2,250 mm², p = 0.045). This is likely due to intensive post-TEM surveillance, which allowed for early detection of recurrence before lesions could grow larger. Other factors, including sex, age, use of coagrasper during the procedure, en-bloc resection, R0 status, and inpatient admission rates, showed no significant differences between groups.

Conclusion

ESD in the anal canal after prior TES appears to be a safe and feasible procedure, with outcomes statistically comparable to those in naïve patients. Although absolute numbers suggest differences, particularly in lesion size, these findings may be influenced by the small sample size. Larger studies are needed to confirm these results and further evaluate long-term efficacy.

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.

Introduction

Gastrointestinal endoscopy is considered a key examination in the setting of anemia workup. However, the yield of esophagogastroduodenoscopy (EGD) and colonoscopy varies depending on the patient's presentation and the type of anemia.

Aims & Methods

The aim of our study was to evaluate the efficiency of EGD and colonoscopy in adult patients with anemia. We retrospectively analysed patients who underwent EGD or colonoscopy for anemia workup in our department between 2018 and 2024. Patients with symptoms suggestive of another cause of anemia were excluded. Additionally, patients who presented with gastrointestinal symptoms and patients with a history of gastrointestinal disease or surgery that could be related to the occurrence of the anemia were also excluded.

Results

A total of 564 patients were included in the study, with a mean age of 72 ±12.8 years. The majority of patients were women (52.8%). 84.9% of the patients underwent EGD, and 49.8% underwent colonoscopy. Overall, 34.8% of patients underwent both examinations. Furthermore, an additional 17.5% were not required to undergo the second examination due to a concrete cause of anemia being found in the initial examination, raising the percentage of patients who completed evaluation to 295 (52.3%). Most of the patients had iron deficiency anemia (IDA) (68.7%). 163 (28.9%) patients had an endoscopic finding that was considered the cause of anemia. EGD yielded significant findings in 119 (24.8%) patients, and colonoscopy in 46 (16.4%) patients. The most prevalent finding of colonoscopy was colon cancer (27 patients), while the most prevalent findings of EGD were peptic ulcer disease (37 patients), stomach cancer (24 patients), and severe atrophic gastritis (18 patients). There was a significant association between the type of anemia and the diagnostic yield of endoscopy, with endoscopic findings being significantly more prevalent in patients with IDA (36.1%) compared to patients without (13.8%) (p < 0.001).

Conclusion

Gastrointestinal endoscopy is the cornerstone examination in patients with unexplained IDA. Conversely, in patients with non-IDA anemia, while endoscopy retains significant diagnostic value, a simultaneous workup for other causes outside the gastrointestinal system is also indicated.

Introduction

Endoscopic submucosal dissection (ESD) is the technique of choice for treating early gastric cancer deemed to have very low risk of lymph node metastasis based on endoscopic evaluation. However, currently, up to 20% of ressected lesions do not meet curative criteria, underlining the importance of patient selection.

Aims & Methods

We aimed to evaluate predictive factors for non curative ressection. We conducted a retrospective cohort study including consecutive gastric epithelial lesions removed by ESD between January of 2005 and June of 2024. Incomplete ESD were excluded. Non curative resection was defined using the high-risk resection criteria from the European Society of Gastrointestinal Endoscopy guidelines. Univariate and multivariate analysis were used to identify predictive factors.

Results

From 990 ESD, 974 were included in the final analysis: median size of lesion 19mm (P25-P75: 15-25), presence of ulceration in 25 (2.8%), deep submucosal invasion in 74 (7.6%), en bloc resection in 944 (96.9%), R0 resection in 901 (92.5%) and non curative resection in 116 (11.9%). In this sample, the following independent predictive factors for non curative resection were identified: location on the superior third of the stomach [adjusted Odds Ratio (aOR) 2.275; IC95% 1.248-4.148], lesion size > 20mm (aOR 4.212; IC95% 2.618-6.775), depressed/ulcerated lesion (aOR 2.394; IC95% 1.328-4.315) or sessile/pedunculated lesion (aOR 4.186; IC95% 2.083-8.411), presence of high-grade dysplasia (aOR 4.372; IC95% 2.139-8.939) or carcinoma (aOR 12.484; IC95% 5.995-25.998) in previous biopsies.

Conclusion

Location, size and morphology of lesion, as well as previous biopsy results are predictive factors for non curative resection, and may assist in decision-making regarding treatment alocation of gastric superficial lesions.

References

Dinis-Ribeiro M, et al. Management of epithelial precancerous conditions and early neoplasia of the stomach (MAPS III): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG) and European Society of Pathology (ESP) Guideline update 2025. Endoscopy, 2025 May;57(5):504-554. doi: 10.1055/a-2529-5025.
Vasconcelos AC, et al. Endoscopic Resection of Early Gastric Cancer and Pre-malignant Gastric Lesions. Cancers, 2023 Jun 7;15(12):3084. doi: 10.3390/cancers15123084.