Clinical Case Summary

Introduction: Neuroendocrine neoplasms (NEN) encompass a heterogeneous spectrum of tumors originating from the diffuse neuroendocrine cell system. Approximately 30% of NEN exhibit functional activity with clinical syndromes through hormone-mediated effects. Synchronous and metachronous functioning syndromes, resulting from the simultaneous release of distinct hormones, are exceptionally rare. Of note, hormonal excess syndromes can have a greater impact on patients` morbidity and mortality than the tumor mass itself.
Case presentation: We present the case of a 49-year-old male patient suffering from an oligo-metastatic ileal NEN, concurrently demonstrating vasointestinal peptide (VIP) and serotonin excretion, complicated by pulmonary tuberculosis, using Racecadotril as ultimate ratio.
After the first cycle of Lutetium-177-DOTATATE peptide-radio-receptor therapy, the patient developed a severe watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome, despite receiving high-dose somatostatin analogues, everolimus, and telotristat ethyl, without any surgical options. The WDHA syndrome necessitated intensive-care-unit (ICU) admission with continual intravenous administration of electrolytes and fluids. With limited alternatives, an off-label intervention utilizing the enkephalinase inhibitor racecadotril (dosage of 100 mg 3x/d) was initiated. After 5 days of treatment, the WDHA syndrome exhibited sufficient control, facilitating the patient's discharge from ICU.
Conclusion: This case report underscores racecadotril as an individualized, off-label treatment strategy for patients with severe VIPoma and serotonin-driven WDHA syndrome, where conventional therapeutic avenues have been exhausted. Further studies are warranted to potentially expand and license the use of Racecadotril in this indication.

Introduction

In colonoscopies with colorectal neoplasia, the endoscopy therapy is recommended. The surveillance (follow-up, FU) colonoscopies follow with the aim to diagnose the recurrent and metachronous lesions. Many guidelines recommend the intervals of such procedures based on the number, size and histopathological phenotype of the resected lesions. In clinical practice, the adherence of the recommendations is variable and selection of the high-risk patients who will benefit from shorter intervals might be helpful. Therefore, detailed study focusing on the development and clinical utilization of the new method combining the clinicopathological phenotype and the mutation burden was started in 2017. The interim results of the clinical phase of the prospective study are described.

Aims & Methods

Patients with colorectal lesions ≥ 10 mm removed by advanced therapeutic methods (en-bloc mucosal resection and submucosal dissection) and followed in interval in year 1, 3 and 5 were included. The therapy and surveillance were performed in one tertiary endoscopy center. The main aim was to assess the metachronous lesions (number, size, locality, histopathology characteristics) in relation with the index colonoscopy findings. Secondary aim was evaluation of the local residual neoplasia (LRN) in the scar after previous therapy.

Results

There were 217 patients included in the study in years 2017 – 2020. Eight of them were excluded because they did not meet the inclusion criteria. Results of the index colonoscopy in 209 patients (130 men, 62,2%; 79 women, 37,8%) were analyzed. 275 index lesions were found, majority of them (238 lesions, 86,5 %, low-grade and high-grade adenomas) were benign and there were 12 (4,4%) intramucosal cancers, two T1 cancers, one T2 cancers and one NET. 21 lesions were hyperplastic or others. Follow-up colonoscopy in one year was performed in 178 patients (82,0%) and in 91 of them (51,1 %) metachronous lesions were found, 120 (64,2%) adenomas, 46 (24,6%) hyperplastic and 21 (11.2%) others, with no cancer. LRN was diagnosed in 5,5% patients. In 122 patients with 3-years FU colonoscopy, 59 (48,4%) had metachronous lesions, mostly adenomas (73; 72,3%), no cancer and one LRN found. 45 patients had 5-years FU colonoscopy so far, 22 of them (48,9%) with metachronous lesions, mostly adenomas (25; 54,3%), no cancer, LRN in one case.

Conclusion

In patients after removal of the high-risk colorectal lesions defined by size ≥ 10 mm, high numbers of metachronous lesions were found in the strict surveillance protocol (years 1, 3, and 5). All the lesions were benign, with no cancer found.

References

Supported by program projects of the Ministry of Health of the Czech Republic with reg. no. NU22-08-00424, MO1012 and Cooperatio.

Introduction

The incidence of rectal neuroendocrine tumors (rNETs) has risen over the past two decades, largely due to the increased use of endoscopic procedures. These tumors are typically small, well-differentiated, and associated with a favorable prognosis. However, up to 82% may be misdiagnosed, leading to inadequate treatment. Accurate staging and appropriate management are essential for achieving long-term, progression-free survival (PFS) [1-2].

Aims & Methods

This study evaluates the clinical outcomes of patients with rNETs ≤1 cm who underwent local excision.
This retrospective, dual-center study included patients with rNETs measuring ≤10 mm who underwent local excision. The primary endpoint was PFS. Resection techniques were categorized into two groups based on guideline recommendations: recommended (m-EMR, ESD, EFTR, and TAMIS/TEMS) or not recommended (biopsy forceps and hot/cold snare polypectomy). Statistical analyses were performed using MedCalc software, with significance set at p < 0.05.

Results

Among 101 patients initially evaluated, 91 were included after excluding 10 due to incomplete endoscopic follow-up. The cohort consisted of 51 men (56%) and 40 women (44%), with a median age of 53 years. The median tumor size was 5 mm (range: 1–10 mm). Tumor grading was G1 in 93.4% of cases and G2 in 6.6%, with a median Ki-67 index of 2%.
Recommended resection techniques were used in 34 patients (37.4%), while 57 patients (62.6%) underwent non-recommended methods. Positive R1 resection margins were found in 27 cases (29.7%), and lymphovascular invasion was detected in two cases. Tumor progression (defined as recurrence, increase in residual tumor following R1 resection, or development of metastasis) occurred in 15 patients (16.5%), with only one case progressing to lymph node metastasis (median time to progression: 14 months [1–108 months]). Two deaths were recorded, neither related to the tumor. The median progression-free survival was 28 months (range: 1–170 months).
Univariate analysis showed that the use of recommended resection techniques significantly improved prognosis (HR 0.12, p = 0.04).

Conclusion

Although rNETs measuring ≤10 mm can recur, their risk of metastatic progression remains low, confirming their indolent behavior. However, early detection and the choice of appropriate resection techniques are essential for optimizing patient outcomes. Guideline-recommended resection methods are linked to a lower risk of progression and should be the preferred approach in clinical practice.

References

1. Rinke A, Ambrosini V, Dromain C, Garcia-Carbonero R, Haji A, Koumarianou A, van Dijkum EN, O'Toole D, Rindi G, Scoazec JY, Ramage J. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for colorectal neuroendocrine tumours. J Neuroendocrinol. 2023 Jun;35(6):e13309.
2. Fine C, Roquin G, Terrebonne E, Lecomte T, Coriat R, Do Cao C, de Mestier L, Coffin E, Cadiot G, Nicolli P, Lepiliez V, Hautefeuille V, Ramos J, Girot P, Dominguez S, Céphise FV, Forestier J, Hervieu V, Pioche M, Walter T. Endoscopic management of 345 small rectal neuroendocrine tumours: A national study from the French group of endocrine tumours (GTE). United European Gastroenterol J. 2019 Oct;7(8):1102- 1112.

Introduction

It has been suggested that the development of cancer chemotherapy resistance may result from the intricate interplay between gene regulation and external environmental factors. Immune biomarkers hold promise as prognostic indicators for the efficacy of chemoradiotherapy; nevertheless, to date, none have been successfully achieved in routine clinical practice.

Aims & Methods

This study is a sub-analysis of data from the prospective IMMUNOREACT 2 trial (NCT04917263) including all the patients who underwent adjuvant therapy. Healthy rectal mucosa adjacent to the cancer was collected during surgery. Gene expression profiling was performed with Nanostring technology using nCounter® PanCancer IO 360™ Panel. Prospectively collected rectal mucosa samples were subjected to flow cytometry to determine the proportion of epithelial cells (Cyt-20⁺) acting as antigen-presenting cells (expressing CD80, CD86, HLA ABC), activated T cells (expressing CD25, CD28, CD38), regulatory T cells (CD4⁺CD25⁺FoxP3⁺) or exhausted T cells (CTLA-4⁺). Non-parametric tests were used for small sample size comparisons. This study aims to evaluate immune biomarkers' role in determining adjuvant therapy's effectiveness in rectal cancer (RC) patients.

Results

A total of 31 patients with RC who underwent adjuvant therapy included in the prospective IMMUNOREACT 2 cohort were analyzed; during a median follow-up time of 20.8 months, 7 patients experienced relapse. Preliminary gene expression analysis on 19 specimens revealed 25 differentially expressed genes between patients who relapsed (n=3) and those who did not (n=16) (Fig. 1 A, B). In particular, in the normal rectal mucosa of patients who relapsed, downregulation of genes associated with macrophages (CD163, CEBPB, MARCO, MS4A2, MS4A4A, MS4A6A, SIGLEC1), inflammation (CCL8, C5, C5AR1, IL11RA, TIE1) and lymphocytes stimulation (VTCN1, TNFSF13B) was observed. Relapse was associated with a high CD8⁺ CD28⁺ cytotoxic lymphocytes mean fluorescence intensity (MFI) (p= 0.05). The accuracy of predicting relapse was AUC=0.765 for CD8⁺CD28⁺ MFI (Fig. 2 A, B).

Conclusion

Our preliminary data suggest that the immune-related markers signature in the healthy peritumoral mucosa might be useful for predicting relapse after adjuvant therapy in rectal cancer patients. Moreover, relapsing patients showed lower stimulation of macrophages and lymphocytes, thus suggesting that impaired immune surveillance might influence adjuvant therapy outcomes. Sampling healthy mucosa might help the decision-making about adjuvant therapy after surgery for rectal cancer.

Introduction

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related death. Most colorectal cancers arise from benign polyps, especially dysplastic adenomas. Colonoscopy with polypectomy is the gold standard for preventing cancer by interrupting the adenoma-carcinoma sequence. This has led to the development of various techniques and devices for improved prevention and treatment. Hot snare endoscopic mucosal resection (HS-EMR), which combines submucosal injections with electrocautery, is commonly used for excising various colorectal polyps. However, it carries risks of diathermy-related complications, such as perforation, and bleeding. To address these issues, cold snare endoscopic mucosal resection (CS-EMR) has been proposed as an alternative. Concerns about residual adenoma/recurrence have been raised with CS-EMR. Therefore, we conducted this meta-analysis to compare the two techniques.

Aims & Methods

We searched electronic databases, including MEDLINE via PubMed, Scopus, Web of Science, and Cochrane, without restrictions on publication date or language. We included RCTs comparing CS-EMR and HS-EMR for colorectal polyp resection. Primary outcomes included the incidence of delayed bleeding and residual/recurrent adenoma (RRA).

Results

On Nov 5, 2024, our literature search across electronic databases retrieved a total of 1,888 records. Following a meticulous screening process, six studies met the eligibility criteria encompassing 1,449 patients and 1,947 polyps. Regarding safety, the overall effect estimates regarding delayed bleeding showed statistically significant results favoring CS-EMR group [OR 0.31, 95 % CI (0.12–0.76), P = 0.01] with no heterogeneity (P = 0.40; I² = 0 %). However, statistical superiority for CS-EMR could not be detected regarding early bleeding [OR 0.78, 95 % CI (0.31–1.97), P = 0.60]. Only two studies reported data on delayed perforation, showing a numerical difference favoring CS-EMR; however, statistical significance could not be obtained [OR 0.26, 95 % CI (0.03–2.41), P = 0.24]. Regarding efficacy, the overall effect estimates regarding complete resection and RRA did not favor either of the groups [OR 0.62, 95 % CI (0.25–1.53), P = 0.30], [OR 2.81, 95 % CI (0.43–18.47), P = 0.28] respectively.

Conclusion

Evidence obtained from this meta-analysis suggests that CS-EMR offers superior safety compared to HS-EMR for colorectal polyp resection. Current evidence remains limited due to the small number of studies included. Therefore, further high-quality randomized controlled trials with larger sample sizes are needed.

References

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• Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med. 1993;329(27):1977–81.

• Facciorusso A, Del Prete V, Antonino M, Buccino VR, Muscatiello N. Efficacy of endoscopic polypectomy techniques for colorectal polyps: a systematic review and network meta-analysis. Gastrointest Endosc. 2020;91(4):733–745.e9.

• Pohl H, Srivastava A, Bensen SP, Anderson P, Rothstein RI, Gordon SR, et al. Incomplete polyp resection during colonoscopy—results of the complete adenoma resection (CARE) study. Gastroenterology. 2013;144(1):74–80.e1.

• Tutticci N, Hewett DG. Cold snare polypectomy: A safe, effective technique for sessile polyps. Gastrointest Endosc Clin N Am. 2015;25(2):291–301.

• Kawamura T, Takeuchi Y, Asawa S, Yokota I, Matsuno T, Omori T, et al. A comparison of cold and hot snare polypectomy for small colorectal polyps: a randomized controlled trial. Am J Gastroenterol. 2018;113(3):403–411.