Introduction

Nivolumab is an anti-programmed death receptor-1 monoclonal antibody, evaluated as monotherapy for advanced HCC in two trials (Checkmate 040¹ and Checkmate 459²). It showed promising results with durable response, good tolerability and a favourable safety profile but failed to demonstrate a statistically significant benefit in overall survival (OS) benefit over sorafenib, the first-line therapy at the time.

Aims & Methods

The objective of this study was to evaluate the efficacy and OS of nivolumab as monotherapy in cirrhotic patients with advanced HCC ineligible for other treatments.
Approval for off-label use was obtained from the hospital committee for each patient based on literature review and personal medical history.
We conducted a retrospective, single-centre study of 22 cirrhotic patients with intermediate or advanced HCC treated off-label with nivolumab between September 2019 and April 2023. Enrolled patients were ineligible for local or surgical therapy, had disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy, and were not eligible for other systemic therapies. All patients received intravenous nivolumab 3 mg/kg once every two weeks for the first 6 months and then 6 mg/kg once every 4 weeks. Treatment was continued until disease progression, serious adverse events, impaired performance status or death.
Outcomes measured were overall survival, radiological response (RR), defined as stable disease, complete or partial response at quarterly abdominal and thoracic CT scans, and biological response (BR), defined as a decrease in alpha-fetoprotein (AFP) blood level of ≥ 25% from baseline after 3 months of therapy. Safety profile of nivolumab was also assessed.

Results

Twenty-two patients were included: 73% male, median age 64.5 years (range: 30-80), 91% Barcelona Clinic Liver Cancer score C, 82% Child-Pugh A. One patient received nivolumab as I-line, 11 as II-line, 8 as III-line and 2 as IV-line. AFP at baseline was available in 19/22 patients and was elevated in 16/19 patients (median 259.9 ng/ml; IQR 26.7-1752). Median time of treatment was 3.5 months (range: 0.4-36.9). OS was 7.8 months (95%CI 4.7-14.2; range 1.1-34.1). RR (defined as partial response or stable disease) at 3 months was achieved in 8 patients and 6 patients maintained it at 6 months. BR at 3 months was achieved in 6 patients.
OS was significantly associated with RR (p 0.002) and BR (p 0.0001) at 3 months. Median OS in patients with RR at 3 months was 27.7 months (95%CI 4.7-27.7) versus 6.4 months (95%CI 3.2-9.1) in patients with disease progression (p 0.0003).
At baseline, better performance status (ECOG 0 vs 1-2) (p 0.031), presence of metastatic lymph nodes (p 0.040) and lower disease burden (monolobar vs bilobar involvement) (p 0.009) were associated with a better OS.
Grade 3-4 adverse events occurred in 5 patients (2 pulmonary thromboembolism, 1 variceal bleeding, 1 autoimmune colitis, 1 severe asthenia).

Conclusion

Nivolumab monotherapy in non-responder or intolerant to TKI patients without any other therapeutic option could represent an acceptable treatment, showing an OS greater than 6 months in 68% of patients (median 7.8 months). RR at 3 months predicts long survivors (median OS 27.7 months), as does BR at 3 months (median OS 27.9 months). Overall, nivolumab was well tolerated.

References

1) Yau T, Kang Y, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020; 6(11)
2) Yau T, Park JW, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. The Lancet Oncology. 2021; 23(1)

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.

Introduction

Esophagogastric junction contractile integral (EGJ-CI) is a metric of EGJ barrier function on high-resolution manometry (HRM), which may be limited by measurement discrepancies and unclear clinical utility. Mean EGJ basal pressure is a novel, simple HRM metric assessing barrier function. We compared their performance to predict conclusive gastroesophageal reflux disease (GERD).

Aims & Methods

Consecutive patients (Nov 2022-Oct 2023) undergoing combined HRM and 24 hour pH-impedance testing OFF antisecretory therapy (except for Barrett's patients) for known or suspected GERD were eligible, all with prior upper endoscopy. Mean (between end-expiration and end-inspiration) basal EGJ pressure, referenced to mean intragastric pressure, was calculated manually using the isobaric contour tool. EGJ-CI was calculated using the smart box tool, with the isobaric contour set 2 mmHg above intragastric pressure, over three respiratory cycles and normalized for its duration. On pH-impedance testing, Lyon classification 2.0 was applied. Conclusive GERD was defined as acid exposure time (AET) >6% or histologically confirmed Barrett’s. Mann-Whitney U and Kruskal-Wallis test, with Bonferroni correction, were used. ROC curves were plotted.

Results

125 patients were included (mean age 51.6 ± 16.5 years, 60% males). Upon applying Lyon 2.0 classification, 45 (36%) patients had conclusive GERD (25 Barrett’s), 7 (6%) borderline GERD, 16 (13%) reflux hypersensitivity (RH), while 57 (45%) had functional symptoms. Patients with conclusive GERD, on HRM, had a significantly lower mean basal EGJ pressure (11.0 vs 18.5 mmHg; p<0.001) than patients without conclusive GERD, while EGJ-CI was not statistically different (26.1 vs 35.1 mmHg∙cm; p=0.101). Mean basal EGJ pressure was significantly different across Lyon v2.0 subgroups (median values in GERD: 11, borderline GERD: 16, RH: 19, FH: 20 mmHg; p<0.001), while EGJ-CI did not differ (p=0.283). Mean basal EGJ pressure (AUROC: 0.73, 95%CI 0.64-0.82) showed greater predictive performance of conclusive GERD than EGJ-CI (AUROC: 0.59, 95%CI 0.49-0.69). The optimal cut-off of 13 mmHg had 72% sensitivity and 62% specificity; a cut-off of 9.5 mmHg had 86% sensitivity, while a cut-off of 23.5 mmHg had 91% specificity.

Conclusion

Mean EGJ basal pressure is a simple HRM metric to predict conclusive GERD, well differentiating GERD phenotypes, with greater performance than EGJ-CI. This metric could be preferred over EGJ-CI as a useful adjunctive measure to support GERD diagnosis.

Introduction

Among the various forms of NOTES (Natural Orifice Transluminal Endoscopic Surgery), Endoscopic Full-Thickness Resection (EFTR) is a minimally invasive endoscopic surgical technique that allows radical resection of epithelial neoplasia with significant fibrosis or suspected deep submucosal invasion.
We describe our initial experience with non-tunnelled exposed EFTR for rectal lesions, with subsequent closure of the defect using an endoscopic suturing device.

Aims & Methods

We performed a retrospective analysis of 11 consecutive patients treated at our centre with non-tunnelled exposed EFTR for removal of 11 lesions located in the distal rectum, below the peritoneal reflection. Indications included 7 recurrences of previous mucosectomy, 1 large circumferential lesion without evidence of submucosal invasion, 2 lesions with suspected submucosal invasion (without imaging evidence of overt muscular invasion) and 1 T3 N0 adenocarcinoma of the pelvic RM treated with neoadjuvant radiotherapy in a patient unfit for surgery. The transmural defect was closed by endoscopic suturing.
Technical success, safety and R0 resection were evaluated.

Results

All lesions were successfully treated by EFTR and no intraoperative or postoperative complications were observed.
EFTR was R0 in 8/11 patients: 1 patient underwent surgery due to high risk of lymph node metastasis.
In 3/11 patients EFTR was R1: in 2 patients the vertical margins were involved by neoplastic tissue and the patients underwent surgery, in 1 patient only the horizontal margins were involved and no endoscopic or histological evidence of recurrence was seen at 12 months.
EFTR proved to be curative in 8 out of 11 patients.

Conclusion

Our initial experience shows that rectal EFTR is a feasible and safe technique, useful for resection of complicated lesions with curative or at least diagnostic intent. Larger randomised trials are needed to better define the clinical benefits and long-term outcomes of rectal EFTR in selected patients.

Introduction

Delayed Gastric Conduit Emptying (DGCE) after Esophagectomy with a gastric conduit is a complication that occurs in 15-39% of patients. It is associated with short and long-term complications and with a poor quality of life. Intra-Pyloric Injection of Botulinum Toxin (BT), Pyloric Pneumatic Dilation (PD), and a combination of these two techniques (BTPD) in the same session, represent the main endoscopic procedures, but comparative data are currently unavailable.

Aims & Methods

Retrospectively analyzed prospectively collected data on all consecutive patients with DGCE after esophagectomy, refractory to prokinetics drugs and treated endoscopically. with BT, PD, or BTPD from January 2014 to November 2023 in San Raffaele Hospital (Milan). International Society Disease of the Esophagus (ISDE) Diagnostic Criteria were used for DGCE diagnosis and classification. Gastric Outlet Obstruction Score (GOOS) was used for clinical staging at diagnosis and at discharge. All patients undergoing BT received 100 UI of toxin, while those undergoing PD were dilated with the same model of pneumatic balloon, progressively inflated from 18 to 20mm, and left in site for one minute for every different size. BTPD underwent BT and BD during the same procedure. Technical success (TS) was defined as the completion of the procedure, clinical success (CS) as the resolution of symptoms/resumption of feeding (soft solid, GOOS 2) at discharge or expanding dietary intake at any rate, without the need to replace the nasogastric tube. Recurrence was defined as symptom relapse after more than 15 days of well-being requiring endoscopic or surgical intervention. Adverse events (AEs) were classified using the AGREE classification.

Results

64 patients (81.2% male, ASA II 54.7%, 90.6% Ivor-Lewis esophagectomy, 77.4% adenocarcinoma), median age 62 years (IR 55-70), were enrolled: 18 (28.1%) in the BT group, 24 (37.5%) in the PD group and 22 (34.4%) in the BTPD group. No statistically significant differences were found in the baseline characteristics among the three groups and in indication, disease stage, neoadjuvant treatments, type of surgery with/without intraoperative pyloric surgical procedures, other surgical complications, and median follow-up. Despite identical TS success (100%), BTPD group exhibited a higher CS rate (100%) compared to the PD and BTPD groups (p=0.02). Among patients who achieved CS, BT group showed a higher recurrence rate (23.1%) compared to the other two groups but not statistically different (p=0.41). Kaplan-Meier dysfunction analysis revealed that the BTPD group was characterized by both a significatively shorter median time to refeeding of 1 day (IR 1-1) compared to the other two groups (log-rank test p=0.0049), and a shorter median time to discharge of 1 day (IR 1-4) (log-rank test p=0.02). No AEs procedures related were recorded.

Conclusion

Endoscopic management of DGCE is challenging and BT and PD represent the main available treatments. Our study shows that the same session combination approach (BTPD) could offer patients a higher rate of clinical efficacy and a shorter time to refeed and to be discharged, maintaining an equivalent safety profile. Further prospective studies are needed to validate these findings.

Introduction

This paired biopsy study aimed to investigate the predictive value of various non-invasive scores for identifying the temporal evolution of hepatic fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).

Aims & Methods

A total of 69 patients with NAFLD who had undergone two paired liver biopsies (mean interval: 21.3 ± 9.7 months) were examined. Fibrosis progression and regression were defined as an increase or decrease of at least one stage in fibrosis between the initial and second biopsy. Fibrosis-4 index (FIB-4), NAFLD Fibrosis Score (NFS), Agile 3+ score, Agile 4 score, and FibroScan-AST (FAST) score were calculated at the time of the initial biopsy.

Results

Upon comparing the results of paired biopsies, 45% of the participants (n = 31) showed no change in fibrosis, 26% (n = 18) experienced fibrosis progression, and 29% (n = 20) had evidence of fibrosis regression. In multivariable logistic regression analysis, the only independent predictive factor for progressive fibrosis was the FAST score. The odds ratio for progressive fibrosis was found to increase by 19% (95% confidence interval: 8–38%, p < 0.05) with every unit increase in FAST score at the time of the initial biopsy. No independent predictors for fibrosis regression were identified.

Conclusion

Patients with higher baseline FAST scores were more likely to experience fibrosis progression independent of potential confounders. Consequently, FAST could serve not only as a diagnostic tool for screening fibrosis in NAFLD, but also as a prognostic indicator.

Introduction

In cirrhosis, several prognostic scores have been developed to predict overall and complication-free survival. The MELD (Model for End-Stage Liver Disease), MELD-Na and MELD3.0 scores have been proposed as a criteria for allocating organs.

Aims & Methods

The aim of our study was to assess the performance of these 3 scores for the prediction of overall and complication-free survival in decompensated Tunisian cirrhotic patients.
Methods: We conducted an observational, retrospective study involving all patients with decompensated cirrhosis managed in Gastroenterology department of Taher Maamouri hospital during the period from January 2010 to December 2021. Mortality was assessed using the Kaplan Meier model. The performance of the scores was assessed using the AUROC (Area under the Receiver Operating Characteristic curve).

Results

One hundred and fifty-two patients were included with an average age of 61 years. Viral liver cirrhosis was the most common (65.13%). The mean value of the MELD-Na and MELD3.0 scores was 17.74 and 19.4, respectively. The mean follow-up time was 17.1 months. The rate of complications and short-term mortality was 33.6% and 18.4% respectively.
The AUROC of the MELD3.0 score in predicting of the occurrence of further decompensation was the highest (0.775) compared to those of the MELD and MELD-Na score (0.743 and 0.756 respectively). The cut-off value of the MELD3.0 score in predicting further decompensation was 20 (sensitivity 60.7%, specificity 73.3%).
In the prediction of 3-month mortality, the AUROCs of the MELD, MELD-Na and MELD3.0 scores were 0.786; 0.841 and 0.850 respectively. The cut-off value of the MELD3.0 score was 24 (sensitivity 68%, specificity 88%). A statistically significant correlation was noted between the MELD3.0 score ≥24 and 3-month mortality (p=0.04).

Conclusion

The MELD3.0 score had the best predictive value for the occurrence of further decompensation and short-term mortality in decompensated cirrhotic patients. Those with a MELD 3.0 score ≥24 should be prioritized on waiting lists.