Clinical Case Summary

Introduction: Endoscopic Full-thickness Resection (EFTR), full-layer resection and suture using a flexible endoscope alone, is less invasive than Laparoscopy and Endoscopy Cooperative Surgery (LECS) because it does not require stromal processing and does not involve vagotomy, and is attracting attention as a new treatment for submucosal tumors(SMT). However, suturing the gastrointestinal tract using a flexible endoscope alone is problematic because the equipment is expensive and the technique is difficult. On the other hand, Laparoscopic Intragastric Surgery (LIGS), developed by Ohashi et al. in 1995, is a highly safe procedure. Combining EFTR with suturing by LIGS (EFTR-LIGS) enables accurate resection and safe suturing, but this has not been reported.
Aim & Methods: LIGS is a procedure in which a single laparoscopic port is created directly into the stomach, the device is inserted, and surgery is performed from the lumen of the stomach as in conventional laparoscopic surgery. In this presentation, we will demonstrate the technique of EFTR-LIGS in two cases. First case was 76 years-old man who was admitted after endoscopic hemostasis for bleeding from GIST in the stomach. On Day 3 of admission, emergency surgery was necessary due to rebleeding. EFTR was selected, as the procedure, though full-layer resection was possible, suturing was not possible due to amount of clot, and the defect was sutured by LIGS. Second case was 75 years-old woman with gastric GIST. After full-layer resection by EFTR, a laceration of the pharynx occurred when retrieval through the pharynx, we performed LIGS to extract the tumor through the abdominal wall and suture the defect.
Results: The average suture time for LIGS is just 5 minutes. There were no complications and average postoperative length was 5days.
Conclusion: The collaboration of EFTR and LIGS is a minimally invasive treatment for that is safe, not difficult and inexpensive, and is very useful procedure for SMT in a stomach.

Introduction

Immunohistochemistry (IHC) is a critical tool for tumor diagnosis and treatment. However, IHC is time consuming and costly, relies on the pathologists’ subjective interpretation. Deep learning has gained ground for predicting the biomarker expression on hematoxylin and eosin (H&E) staining images. In this study, we aim to create an automatic pipeline for the construction of deep learning models to generate virtual IHC output using H&E whole slide images and validate its clinical applicability by reader study.

Aims & Methods

We obtained 134 whole-slide images (WSIs) from 73 patients at Renmin Hospital of Wuhan University and extracted 415,463 patches from H&E-stained WSIs. Our study focused on five widely used biomarkers in pathology reports, namely anti-P40, CK-pan, Desmin, P53, and Ki-67, as recommended by the NCCN guidelines. We validated these models by using independent whole-slide images (WSIs). The number of WSIs used for each model were as follows: model-P40 (6 WSIs, 38389 Patches), model-PCK (9 WSIs, 72443 Patches), model-Ki67 (7 WSIs, 53162 Patches), model-Desmin (5 WSIs, 23974 Patches), and model-P53 (5 WSIs, 36822 Patches). We aimed to predict these biomarkers expression in H&E WSIs and quantify the percentage of Ki-67. There are three main steps: Firstly, we employed HEMnet neural network to align the corresponding IHC and H&E WSIs, transfering the molecular labels from IHC to H&E images. Secondly, pathologists reviewed the annotations made by HEMnet and corrected HE-IHC mismatched tiles using VIA labelling platform. Lastly, the deep learning models were trained to predict positive tiles. The performance of models was assessed by sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC). To assess the applicability of models, we randomly selected 30 cases including H&E and IHC WSIs for three pathologists to write the reports in the reader study by reading the interpretation of real IHC and AI-generated IHC.

Results

The sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) of the models for classifying positive pixels of each biomarker was: P40 (91.64%, 87.39%, 88.66%, AUC: 0.95), PAN-CK (92.40%, 89.35%, 90.81%, AUC: 0.96), Ki67 (89.63%, 86.04%, 86.77%, AUC: 0.95), Desmin (91.44%, 88.11%, 89.17%, AUC: 0.96), and P53 (75.44%,86.52%,83.04%, AUC: 0.90). The predicted Ki-67 percentage was comparable to the assessments made by expert pathologists, with a difference ranging from 7.00%±3.69%. In the reader study, compared with real-IHC pathology report, the accuracy of AI-IHC pathology report of each biomarker was: Desmin(100%,66/66), Pan-CK(98.3% , 59/60), P53(98.3% ,59/60), T-stage(84.8% .56/66), P40(96.7% ,29/30). and there is no significant difference between the quatification of Ki-67 score(t= 0.253 ,P= 0.800).
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Conclusion

Our deep learning models have demonstrated promising performance in predicting gastrointestinal tumor biomarkers based on H&E slides. The utilization of these models can alleviate the burden of IHC staining and clinicopathological assessments. Furthermore, these models have the potential to aid in patient grading, facilitate informed treatment decisions, and provide valuable prognostic assessments.

Disclosure

There is no conflict of interest in this abstract.

Introduction

Antagonism of the interaction between the cellular adhesion integrin ɑ4β7 and endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) has proven to be relatively safe and effective in the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). Additional benefit may be gained from an ɑ4β7 antagonist given via the subcutaneous (SC) route at extended intervals (eg, every 8 to 12 weeks) during maintenance therapy.

Aims & Methods

The humanized monoclonal IgG1 antibody SPY001 binds to the same ɑ4β7 epitope as vedolizumab and includes a YTE modification within the Fc region to increase its serum half-life via increased affinity for the neonatal Fc receptor (FcRn), thereby favoring recycling into the circulation over degradation. The binding affinity of SPY001 to ɑ4β7 was determined by kinetic exclusion assay (KinExA), surface plasmon resonance, and flow cytometry. In vitro functional activity was determined by inhibition of MAdCAM-1-mediated cell adhesion. In vivo half-life extension was evaluated via pharmacokinetic analysis in Tg276 transgenic mice (hemizygous for human FcRn) and in non-human primates (NHP). PK simulations in humans were based on allometric scaling of SPY001 clearance observed in NHP. Safety was assessed via a good laboratory practice toxicity (GLP-tox) study in NHP.

Results

SPY001 binds specifically to ɑ4β7 and not to the related integrins ɑ4β1 and ɑEβ7. In cell-based binding assays, SPY001 binds ɑ4β7 expressed on the surface of RPMI-8866 cells with an affinity matching that of vedolizumab, but does not bind to Ramos cells expressing ɑ4β1. It demonstrates high affinity for ɑ4β7, with a K_D of <1 nM. Functionally, SPY001 potently inhibits MAdCAM-1-mediated cell adhesion with an IC₅₀ comparable to that of vedolizumab but has no inhibitory activity for VCAM-1-mediated cell adhesion.

In Tg276 mice, the half-life of SPY001 was approximately 12 days compared to approximately 4 days for vedolizumab. In cynomolgus monkeys, the half-life of SPY001 was approximately 22 days following a single SC infusion, substantially longer than the half-life of vedolizumab (~6 days) in the same study. Based on allometric scaling of SPY001 clearance observed in this study, predictive simulations of SPY001 PK in humans suggest that Q8W-Q12W SC dosing will achieve therapeutic exposure in patients across a wide range of body weights and albumin concentrations. In a repeat-dose GLP toxicity study in NHP no adverse or dose limiting toxicities were observed even at the highest dose tested. Both SC and IV administration were well-tolerated and observations related to the administration procedure were similar across doses including controls.

Conclusion

SPY001 is a novel humanized monoclonal IgG1 with an extended half-life relative to that of vedolizumab in Tg276 mice and cynomolgus monkeys. Repeat-dose toxicity studies at doses up to 160 mg/kg showed no SPY001-related adverse events and a safety profile supportive of progression into clinical development. SPY001 offers the potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Clinical studies are warranted to demonstrate this potential.

Disclosure

EZ, DR, RV, JO, and HS are employees of Paragon Therapeutics.
JF, DN, AS, MR, and OB are employees of Spyre Therapeutics.