MICROSATELLITE INSTABILITY ON THE PROGNOSIS AND EFFICACY TO CHEMOTHERAPY IN GASTRIC CANCER PATIENTS: A PROPENSITY SCORE-MATCHED STUDY

Introduction
Toupet fundoplication (TF) has been shown to have fewer adverse effects compared to Nissen fundoplication (NF), however, it is unknown whether the advantages of TF persist when comparing outcomes by the distensibility of post-fundoplication lower esophageal sphincter (LES). Therefore, we aimed to compare quality of life (QOL) outcomes between NF and TF according to distensibility index (DI) measured by intraoperative endoluminal impedance planimetry.

Methods
This is a retrospective study of a prospectively maintained database of patients who underwent laparoscopic NF or TF, intraoperative EndoFLIP, and self-reported QOL outcomes postoperatively at 3-weeks, 6-months, 1-year, and 2-years using RSI, GERD-HQRL, and dysphagia surveys. Comparisons were made using chi-square and Wilcoxon rank-sum tests.

Results
From 2018 to 2021, 303 patients were analyzed (68% female) who underwent NF (n=80) and or TF (n= 223) for treatment of GERD, including paraesophageal hernia which represented 65% of cases. Of those who returned postoperative surveys, at 30mL fill-volumes, there were a total of 20 NF versus 25 TF with DI <2.0mm²/mmHg, 32 NF versus 71 TF with DI 2.0-3.5mm²/mmHg, and 13 NF versus 89 TF with DI>3.5 mm²/mmHg. At the optimal DI range of 2.0-3.5 mm²/mmHg at 30mL fill, no statistical differences were found on analysis at 3-weeks, 6-months, 1-year, and 2-year timepoints when evaluating RSI, GERD HQRL, gasbloat, and dysphagia scores. No statistical differences were found on QOL comparisons of NF versus TF within DI ranges <2.0mm²/mmHg or DI> 3.5mm²/mmHg at any timepoint (Table 1). At 40ml fill volume, there was a total of 20 NF versus 25 TF at DI < 2.0mm²/mmHg, 32 NF versus 71 TF with DI 2.0-3.5 mm²/mmHg, and 13 NF versus 89 TF at DI >3.5 mm²/mmHg. Analysis of postoperative surveys demonstrated no statistical differences when comparing RSI, GERD-HQRL, gasbloat and dysphagia scores of NF versus TF according to DI range <2.0mm²/mmHg, 2.0-3.5mm²/mmHg (Figure 1), or >3.5mm²/mmHg at any postoperative timepoint.

Conclusion
Impedance planimetry appears to be an objective measure of the physiology of the LES before, during, and after fundoplication. NF is comparable to TF when compared according to DI range, suggesting that QOL outcomes are dependent on post-fundoplication LES distensibility rather than type of fundoplication.

Background: Assessing patients following Laparoscopic Fundoplication (LF) can be challenging. The role of High-Resolution Manometry (HRM) performed after LF is still unclear and debated. We sought to determine the HRM parameters of a functioning fundoplication and evaluate whether HRM could discriminate it from a tight or a defective one.

Methods: Patients who underwent laparoscopic Nissen (LN) or Toupet (LT) fundoplication for GERD between 2009-2022 were included. Symptoms were scored using a dedicated symptom score (SS). HRM and 24-h pH monitoring (pH) were performed before and 6 months after surgery, regardless of patients’ symptoms; > 3cm hiatal hernias were excluded. LF failure was defined as GERD symptom recurrence (SS >8) and/or an abnormal 24h-pH. The study population was divided in 5 groups: LN and LT patients with normal 24h-pH (LN pH- and LT pH+, respectively), LN and LT patients with pathological 24h-pH (LN pH+ and LT pH+ groups, respectively) and patients having a postoperative dysphagia score with an intensity > 2 (Dysph group). LES parameters (resting pressure, IRP, total and abdominal length), and esophageal body function were reviewed by 2 experts (RS,GC). Differences in the postoperative HRM metrics between groups were evaluated, irrespective of preoperative ones.

Results: During the study period, 123 patients (M:F=84:39) having pre- and postoperative HRM were recruited (figure 1): 89 showed no objective sign of GERD recurrence after LN (LN pH-: 41 patients) or LT (LT pH-: 48 patients); 21 showed an abnormal postoperative 24h-pH after LN (LN pH+: 15 patients) and LT (LT pH+: 6 patients). Five patients (all had LN) reported postoperative dysphagia (Dysph). Eight patients with GERD symptoms despite a normal 24h-pH were excluded from further analysis. LES resting pressure and total and intra-abdominal lengths were significantly lower in the LN pH+ group compared to the LN pH-, as well as LES resting pressure and abdominal length in the LT pH+ group compared to the LT pH-. The percentage of ineffective swallows was significantly higher in the LT pH- compared to LN pH-. No other differences were detected in the esophageal body motility. Furthermore, LT pH- patients showed a significantly lower LES resting pressure and IRP compared to LN pH-. Conversely, IRP was significantly higher in Dysph compared to LN pH-. All data are showed in table 1.

Conclusion: This study provides the benchmark HRM values for an effective LF and confirms that the evaluation of the neo-sphincter with HRM improves the clinical assessment of symptoms recurrence and can discern patients with a well-functioning wrap from those showing GERD recurrence for an ineffective one. Moreover, IRP significantly correlated with the occurrence of postoperative dysphagia. Even if effective, LT was associated with significantly lower LES resting pressure and IRP than LN.

Introduction:
Abnormal DeMeester score on esophageal pH-monitoring is a well-established predictor of favorable outcome for antireflux surgery (ARS). Esophageal pH monitoring also facilitates analysis of the temporal association between symptoms and reflux episodes. This association can be expressed with several symptom-reflux association indices, symptom association probability (SAP) being the most reliable. SAP is often used as an adjunct to DeMeester score during risk stratification prior to ARS. However, the utility of SAP in predicting ARS outcome has not been well established. The aim of this study was to determine the impact of SAP as an adjunct to DeMeester score in predicting outcomes after fundoplication for GERD.

Methods:
Records of patients who underwent primary (full or partial) fundoplication at our institution from 2015 to 2021 were reviewed. Patients with a preoperative DeMeester score > 14.7 on Bravo pH monitoring and a documented SAP for up to 3 symptoms were included. The SAP was considered positive if the calculated value was >95%, indicating the likelihood of a chance association between the reflux event and the symptom was <5%.
Patients completed the gastroesophageal reflux disease health-related quality of life (GERD-HRQL) questionnaire pre- and postoperatively. Favorable outcome was defined as freedom from proton pump inhibitor (PPI) and patient satisfaction at 1 year postoperatively. The presence and number of positive SAP, as well as positive SAP for individual symptoms and combined typical and atypical symptoms were evaluated for an association with surgical outcomes.

Results:
The final study population consisted of 360 patients (72.2% female) with a median (IQR) age of 60.0 (52-67). At a median (IQR) follow-up of 24.1 (13-46) months, 88.2% patients achieved favorable outcome, freedom from PPI was 88.9%, satisfaction was 86.7%, and 74.1% had at least 50% improvement in their GERD-HRQL score.
SAP was positive in 264 (73.3%) patients, of which 127 (48.1%) had one SAP positive symptom, 107 (40.5%) had two SAP positive symptoms, and 30 (11.4%) had all three SAP positive symptoms. There was no association between having at least one positive SAP symptom and favorable outcome (p=0.500), freedom from PPI (p=0.448), satisfaction (0.567), or 50% improvement in GERD-HRQL (p=0.375). There was no difference in favorable outcome between patients with one, two or all SAP positive symptoms (0.721). No association with favorable outcome was found among patients with positive SAP for typical symptoms (p=0.872) and atypical symptoms (p=0.819) or any of the individual symptoms.

Conclusion:
Symptom association probability did not add any value to a positive DeMeester score for risk stratification prior to antireflux surgery. These findings suggest that SAP should not be used in surgical decision-making in patients with objective evidence of reflux.

INTRODUCTION
Tumor-infiltrating lymphocytes (TILs) play a regulatory role in the tumor-associated immune response and are important in the prognosis and treatment response of several cancer types. However, due to its heterogeneity, the prognostic value of TILs in gastric cancer (GC) is still controversial. Thus, this study aimed to investigate the association between the density of TILs and patients’ outcomes in GC.
METHODS
Patients with gastric adenocarcinoma who underwent curative intent gastrectomy at our Institute between 2009 and 2019 were retrospectively investigated to perform tissue microarrays. Expression of CD3+ TILs was conducted by immunohistochemical (IHC) and determined by the percentage of positive-stained cells. TIL evaluation was conducted according to TILs intensity (4-point), and the percentage of CD3+ T cells infiltration was classified into a 4-point score based on quartiles. The final score was determined by the sum of the two scores (0-8 points). A score≥4+ was defined as a high-CD3+ expression. Microsatellite instability (MSI), CD4+/CD8+ T cells ratio, and PD-L1 were also evaluated by IHC.
RESULTS
A total of 345 patients with GC were enrolled. The median percentage of staining cells for TILs CD3+ was 48.3% (42.5 – 55). Accordingly, 124 (35.9%) GCs were classified as low-CD3+ and 221 (64.1%) as a high-CD3+ group. Clinical and surgical characteristics were similar between both groups. Poorly differentiated histology (p=0.014), Epstein-Barr virus (EBV) positivity (p<0.001), PD-L1 positive (p=0.001), and CD4<CD8 (p<0.001) were associated with high-CD3+ GC. There was no difference regarding MSI status, pT, pN, and pTNM stage between low- and high-CD3+ groups. In survival analysis, the high-CD3+ group had better disease-free survival (DFS) and overall survival (OS) rates compared to the low-CD3+ GC (p=0.055 and p=0.041, respectively). In the multivariate analysis, total gastrectomy, lymph node metastasis, advanced pT stage, and low-CD3+ were independent factors related to worse survival for both DFS and OS. MSI and CD4+/CD8+ ratio were not significantly associated with survival.
CONCLUSIONS
1. High CD3+ TILs were significantly associated with improved survival and could serve as prognostic biomarkers in GC. 2. CD3+ T cells infiltration was related to both EBV and PD-L1 positive GC and may also assist in the investigation of targets in immunotherapy.

INTRODUCTION
Microsatellite instability (MSI) gastric cancer (GC) generally has a better prognosis and no benefit in survival with chemotherapy (CMT) than microsatellite stable (MSS) GC. However, patients with MSI GC have distinct clinicopathological characteristics consisting of factors predicting positive and negative outcomes, such as less lymph node metastasis and older age patients. Therefore, measuring the value of MSI as a prognostic factor after controlling for these discrepant factors is necessary to determine the real impact of MSI/MSS status on survival. Thus, this study aimed to compare the survival of GC with MSI and MSS using Propensity Score Matching (PSM) to reduce the biases of clinicopathological features. We further analyzed the efficacy of CMT in the MSI population.
METHODS
We reviewed all GC patients who underwent curative gastrectomy. Patients were divided into MSI and MSS groups. PSM including 8 variables (sex, age, comorbidities, ASA, type of gastrectomy pT, pN and CMT) was used to match clinicopathological factors between the two groups.
RESULTS
Among the 378 patients enrolled, 78 (20.6%) had MSI. Older age (p<0.001), subtotal gastrectomy (p=0.008), pN0 (p=0.020), and earlier stage tumors (p=0.012) were associated to MSI GC. Survival analysis showed better disease-free survival (DFS) and overall survival (OS) in the MSI group (p=0.012 and p=0.019, respectively). After PSM, 78 patients were matched in each group. All variables assigned in the score were well matched, and both groups became equivalent regarding age (p=0.741), type of gastrectomy (p=0.510), pT (p=0.744), pN (p=0.336), and pTNM (p=0.244). After the matching, the DFS and OS differences by MSI status were estimated to be larger than before (DFS: 63.3% vs 41.4% p=0.002; OS: 65.8 vs 42.5%, p=0.002). Regarding MSI patients referred for CMT (n:60; stage>IB), 51.7% received CMT (MSI+CMT) and the others were treated with surgery alone (MSI+SURG). There was no difference in DFS and OS between both groups (p=0.255 and p=0.178, respectively). Also, recurrence-free survival was equivalent in MSI+CMT and MSI+SURG groups (72.1% vs 66.9%, p=0.638). Survival analyses demonstrate that DFS and OS of MSI+SURG were similar to MSS GC who received CMT (p=0.869 and p=0.706, respectively).
CONCLUSIONS
1.Even after controlling for clinicopathological characteristics, MSI was a strong prognostic factor. 2. MSI GC showed no significant survival benefit with the addition of CMT.