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

Gastrointestinal involvement is common in patients with multiple sclerosis (MS). It is estimated that 35–54% of MS patients experience constipation, while 29–51% develop faecal incontinence (FI), with both conditions frequently coexisting¹. The underlying pathophysiology is complex, as MS can affect the central nervous system at multiple levels. Despite its high prevalence and significant impact on quality of life, few studies have specifically addressed anorectal dysfunction in these patients.
The aim of our study was to describe the clinical and manometric features of MS patients presenting with constipation and/or FI.

Aims & Methods

26 patients with MS were included. High-resolution anorectal manometry (HRAM; Medtronic®), following the London protocol, and balloon expulsion test (BET; Matla Systems®) were performed in all subjects. Reference values were derived from 20 healthy controls assessed at our centre (Table 1).

Table 1. HRAM Parameters in Healthy Subjects in left lateral decubitus

Results

Faecal incontinence was observed in 21 patients (80.8%), predominantly mixed (42.3%), complete (stool and gas; 34.6%), and with Wexner scores >9 in 26.9% of cases. Constipation was reported by 15 patients (57.7%), of whom 14 (53.8%) perceived obstructive defecation. Constipation and FI coexisted in 10 patients (38%). Urinary incontinence was also present in 17 patients (65.4%).
Manometric findings revealed a tendency towards resting anal sphincter hypotonia (67.06 ± 19.85 mmHg) and reduced maximum voluntary contraction pressure (median 105.35 mmHg [IQR 86.48–149.28 mmHg]). Median contraction duration was 30 seconds (IQR 8–32 s). Rectal sensitivity assessment showed median thresholds for first sensation at 55 cc (IQR 40–70 cc), second sensation at 125 cc (IQR 100–160 cc), and maximum tolerated volume at 170 cc (IQR 135–190 cc). Sensory abnormalities were identified in 11 patients (42.3%), 4 due to hypersensitivity (15.4%) and 7 (26.9%) due to hyposensitivity.
An impaired push manoeuvre was observed in 20 patients (83.3%): type I dyssynergic defecation (DD) in 5 patients (20.8%), type II in 5 (20.8%), type III in 4 (16.7%), and type IV in 6 (25%). BET confirmed dyssynergia in 10 patients (41.7%).
*Note: Results are expressed as mean ± standard deviation or median (interquartile range), depending on data distribution. Reference values are presented as mean ± standard deviation.*

Conclusion

FI was the most prevalent symptom, often coexisting with constipation and obstructive defecation. The tendency observed in manometric findings towards anal hypotonia and hypocontractility, as well as the presence of dyssynergia in a significant number of patients, may allow the selection of individuals suitable for targeted therapies.

References

1. Dibley L, Coggrave M, McClurg D, Woodward S, Norton C. "It's just horrible": a qualitative study of patients' and carers' experiences of bowel dysfunction in multiple sclerosis. J Neurol. 2017 Jul;264(7):1354-1361.

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

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

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.