Introduction

Computer-aided detection (CADe) system increases the efficiency of adenoma detection during colonoscopy, which is expected to reduce the incidence of colorectal cancer as well as cancer treatment-associated medical costs. However, most lesions detected using CADe have been reported to be diminutive adenomas that may not affect patient prognosis. Additionally, CADe may impose an immediate economic burden because the system needs to be purchased. Consequently, the use of CADe for all colonoscopy procedures seems impractical. This study aimed to evaluate the usefulness of CADe in patients undergoing regular surveillance colonoscopy (SCS), to identify the characteristics of endoscopists and patients who may benefit significantly from CADe.

Aims & Methods

Patients who underwent regular SCS with CADe at Hiroshima University Hospital from January to March 2023 and had undergone colonoscopy at least twice in the previous three years using a conventional detection method were enrolled. Forty-eight endoscopists who had collectively performed ≥800 colonoscopies performed the examinations. Endoscopic resection was performed for lesions ≥6 mm in size, flat and depressed neoplastic lesions ≤5 mm in size, and lesions with suspected high-grade dysplasia or T1a carcinoma, according to Japanese guidelines. Diminutive polypoid adenomas ≤5 mm in size were followed up without resection. Lesions pathologically identified as adenomas >6 mm or carcinomas were defined as index lesions (ILs). Lesions pathologically identified as adenomas ≥10 mm in size, tubulovillous adenomas, and high-grade dysplasia were defined as advanced adenomas (AAs). The clinicopathological findings of the lesions detected by CADe were evaluated, and the outcomes were compared between the semi-clean colon (diminutive polypoid adenomas ≤5 mm in size followed up without resection) and clean colon (no adenomatous polyps) groups.

Results

Overall, 78 patients were included. CADe identified 46 adenomas that were not detected by previous colonoscopy in 28 patients, including three ILs but no AAs. The mean withdrawal time was 824 ± 353 s, and the mean tumor diameter was 3.3 mm (range, 2–8 mm). The most common gross type was 0-Is (70%), followed by 0-Isp (17%) and 0-IIa (13%). Most tumors were located in the ascending and sigmoid colons (28%), followed by the transverse colon (26%), cecum (7%), descending colon (7%), and rectum (4%). The ILs were 0-Isp Isp of 6 mm diameter in the ascending colon, 0-Is of 7 mm diameter in the transverse colon, and 0-Isp Isp of 6 mm diameter in the descending colon, all of which were adenomas with lesions on the folds. Overall, 34.1% and 38.2% of the patients in the semi-clean and clean colon groups, respectively, had newly detected adenomas. No new neoplastic lesions were detected using CADe in patients without a history of endoscopic resection. When comparing the clinical backgrounds of patients with and without new ILs detected in CADe SCS, a significant difference was found in the IL detection rate at the previous SCS between the groups (67% vs. 12%, p = 0.0319).

Conclusion

CADe may help detect adenoma in SCS for patients with semi-clean colons and those with clean colons and a history of endoscopic resection. Its effectiveness is considered more for patients with ILs at the previous SCS.

Introduction

Biologic therapies such as anti-TNF-alpha agents (infliximab, adalimumab), interleukin modulators, and gut-selective integrin antagonists like vedolizumab have significantly improved outcomes in inflammatory bowel disease (IBD), leading to enduring remission, better quality of life, and reduced surgical intervention and hospitalizations. However, many patients may eventually lose response, often due to factors like the formation of anti-drug antibodies, altered drug metabolism, or individual patient characteristics. Dose escalation—by increasing dosage or reducing intervals—is commonly used to counteract this loss, especially for anti-TNF therapies guided by therapeutic drug monitoring. Vedolizumab poses a greater challenge in this regard due to the lack of standardized monitoring protocols. We aimed to investigate the effectiveness of dose-escalated infliximab, adalimumab, and vedolizumab in IBD patients who worsened after initial response, evaluating outcomes such as treatment persistence and clinical remission, to guide more personalized, cost-effective treatment strategies.

Aims & Methods

We conducted a retrospective analysis of IBD patients who underwent Infliximab (IFX), vedolizumab, or adalimumab (ADA) therapy dose escalation between 2020-2024 at a tertiary IBD centre. Primary outcomes included clinical remission using disease activity scores (Simple Clinical Colitis Activity/SCCAI Index for UC, Harvey-Bradshaw Index/HBI for CD), biochemical markers (CRP, faecal calprotectin) and treatment persistence, evaluated at 3-12 months, 12 months, and annually up to 36 months post-escalation.

Results

A total of 155 patients (median age 31 years, 46% female) were included, of which 89 patients (57%) were prescribed dose-escalated IFX, 48 patients (31%) were prescribed dose-escalated ADA and 18 patients (12%) were prescribed dose-escalated Vedolizumab. Of those included, 118 patients (76%) had Crohn’s disease, 36 patients (23%) had ulcerative colitis (UC) and 1 patient (1%) had indeterminate disease. Indications for dose escalation included secondary loss of response (SLOR) (105/155; 68%) and/or low drug levels (65/155; 42%). Dose-escalated IFX led to significant improvements in disease activity scores at 3 months (HBI: p=0.002; SCCAI: p=0.0003). Improvement in SCCAI was maintained at 12 months (p=0.00007), 2 years (p=0.0008) and 3 years (p=0.025). Improvement in HBI was maintained at 2 years (p=0.01) and 3 years (p=0.049). Significant improvement in CRP following dose-escalated IFX was reported at 3 months (p=0.011), 12 months (p=0.004), 2 years (p=0.006) and 3 years (p=0.03). Dose-escalated ADA led to a significant improvement in HBI at 3 months (p=0.023). This improvement was maintained at 12 months (p=0.005) and 2 years (p=0.008). Early improvement in faecal calprotectin was reported at 3 months (p=0.046). Significant initial improvement in SCCAI following dose-escalated Vedolizumab was reported at 3 months (p=0.043). This improvement was not maintained at any further follow-up points (p>0.05). Minor adverse events were reported in 3 patients receiving dose escalated ADA and in 6 patients receiving dose escalated IFX.

Conclusion

Our study demonstrates that biologic dose escalation is an effective and safe mechanism to recapture clinical remission, with high rates of treatment persistence.

Introduction

Wee1 negatively regulates the G2/M checkpoint of the cell cycle, inhibiting cells with DNA damage from entering mitosis and inducing apoptosis. Although efficacy of Wee1 inhibitors as single agents or in combination with other agents has been reported in a variety of carcinomas and the association between Wee1 inhibitors and tumor immunity has been reported, the effect of Wee1 inhibitors on the tumor immune microenvironment in colorectal cancer (CRC) has not been clarified. Since p53 and KRAS are involved in cell cycle regulation at the G1/S checkpoint, mutations in them may increase dependence on the G2/M checkpoint for DNA repair, making Wee1 inhibitors more effective.

Aims & Methods

This study aimed to clarify the association between Wee1 expression and clinicopathological features in CRC and the effect of Wee1 inhibitors on the tumor immune microenvironment in CRC. Study 1: We performed immunostaining on 152 CRC cases surgically resected at our hospital between May 2013 and February 2015, and classified them into positive and negative groups according to the degree of Wee1 expression and investigated the association between Wee1 expression and clinicopathological features. Study 2: We measured Wee1 expression levels by Realtime PCR on 10 human-derived CRC cell lines and 2 mouse-derived CRC cell lines. We examined the effect of Wee1 inhibitor (AZD1775) on cell proliferation using Timelapse system. We examined the effect of Wee1 inhibitor on cell cycle using Cell Cycle Analysis Kit. We examined the effects of Wee1 inhibitor on apoptosis induction were examined using the Apoptosis Detection Kit. Study 3: We created the CRC orthotopic transplantation mouse model by transplanting the CRC cell line MC38 derived from C57BL/6 mice into the cecum of mice, comparing the tumor sizes of the control and treatment groups treated with Wee1 inhibitor for 21 days, and evaluating the effect of Wee1 inhibitor on the tumor immune microenvironment by immunostaining and RNA sequencing of mice tumor specimens.

Results

Study 1: No significant association was found between Wee1 expression and clinicopathological features or prognosis. However, overall survival rate was significantly higher in Wee1 positive and KRAS-mutant patients compared to Wee1 negative and KRAS wild-type patients. Study 2: Real time PCR showed that Wee1 expression was higher in most CRC cell lines than in normal colon mucosa. Wee1 inhibitor attenuated cell proliferation in a concentration-dependent manner in all CRC cell lines, and the effect was independent on Wee1 expression level. Cell cycle analysis showed that the percentage of cells in G2/M phase increased after exposure to Wee1 inhibitor, especially in cell lines with both p53 and KRAS mutations. In addition, the number of apoptotic cells increased after exposure to Wee1 inhibitor, but in the cell lines with KRAS mutation and p53 wild type, the number of apoptotic cells did not increase. Study 3: In the orthotopic transplanted mouse model, tumor volume was significantly smaller in the treated group compared to the control group, and immunohistological examination and RNA sequencing of mice tumor specimens showed enhanced tumor immunity and suppressed stromal reaction.

Conclusion

Wee1 inhibitor attenuated CRC cell proliferation through modulating cell cycle, especially in cell lines with p53 mutation and attenuated tumor growth via enhancement of tumor immune response and suppression of stromal reaction in orthotopic transplanted mouse model. Wee1 inhibitor AZD1775 could be the promising treatment option for CRC.

Introduction

In addition to colonoscopy and histology, endoscopic ultrasound (EUS) plays a pivotal role in assessing rectal cancer (T-staging). As new therapeutic options emerge, exact imaging of the tumor is essential for the primary diagnosis and the evaluation of therapeutic response. In this regard, optical coherence tomography (OCT) offers a superior axial and lateral resolution compared to conventional rectal EUS and may contribute to individualized therapeutic strategies.

Aims & Methods

Our study aimed to evaluate the imaging quality of our further refined OCT-rectoscope prototype, which integrates an extended range additional to the optimized standard mode.
We integrated a double ferrule design with a fiber optical switch into a MHz-OCT rectoscope.
The performance of this adjustable OCT-rectoscope was assessed in two human colons, post-mortem and in situ. The body donors were preserved using an ethanol-glycerol-lysoformin-based technique resulting in true-to-life tissue consistency.

Results

The extended range mode adjusted the focus depth and imaging range and ensured imaging quality despite varying colon diameters or altered total wall thickness. The optimized standard mode gave a detailed resolution of the different rectal wall layers. Compared to the former prototype MHz-OCT rectoscope and rectal EUS, the images stood out: The mucosa appeared as a broad pale gray band, exactly circumscribed by the lamina muscularis mucosae. The submucosa was visualized as an inhomogeneous, light gray broad area. Furthermore, the muscularis propria comprising the circular and longitudinal muscle layer manifested as two homogeneous dark gray bands. The serosa was displayed as a bright band.

Conclusion

The new dual-mode MHz-OCT design allows a fast change between the extended range and the optimized standard mode. The imaging quality in both modes was exceptional compared to the state of the art EUS, with clear delineation of the different rectal wall layers, providing ideal conditions for accurate staging of rectal cancer. Further imaging studies are warranted to evaluate this dual-mode MHz-OCT rectoscope in human colons in vivo. In the future, this technique could serve additionally in indications like inflammatory bowel disease to quantify inflammation more precisely. Moreover, it could be integrated into a colonoscope design to evaluate the whole colon.

References

B. Schulte*, M. Göb* et al., High-resolution rectoscopy using MHz optical coherence tomography: a step towards real time 3D endoscopy. Scientific Reports, 02/2024
AP. Singh et al., Virtual Hall sensor triggered multi-MHz endoscopic OCT imaging for stable real-time visualization. Opt express, 02/2024

Introduction

Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking drug indicated for ulcerative colitis (UC), is administered intravenously at Weeks 0, 2, and 6, then every 8 weeks (Q8W). Dose escalation to every 4 weeks (Q4W) may recapture response to treatment in ~50% of patients with inadequate response. Real-world outcomes and factors associated with VDZ dose escalation from Q8W to Q4W remain underexplored.

Aims & Methods

Adults with moderate to severe UC initiating VDZ Q8W maintenance were prospectively followed in a Canadian patient support program (2015-2023). Two cohorts were included: 1) patients escalated to Q4W during maintenance after week 14 infusion (Q8W>Q4W maintenance) and 2) patients maintained on Q8W treatment for ≥2 years without escalating (Q8W maintenance). Rates of clinical remission (partial Mayo Score [PMS]<3) were described by prior biologic experience. Associations between baseline characteristics and clinical remission 3 months after Q4W dose escalation were assessed using Wilcoxon rank sum test and Fisher’s exact test. Treatment persistence at 12 and 24 months after initiation and dose escalation were evaluated in Q8W>Q4W maintenance using Kaplan-Meier survival analysis.

Results

373 patients (68% bio-naïve) and 300 patients (72% bio-naïve) were included in the Q8W>Q4W maintenance and Q8W maintenance cohorts, respectively. Median age at treatment initiation was 47 years in Q8W>Q4W maintenance and 48 years in Q8W maintenance. Both cohorts had a median baseline PMS score of 6. In Q8W>Q4W maintenance, median disease duration before treatment initiation was 4 years and median follow-up was 19 months. In Q8W maintenance, median disease and follow-up duration were 5 years and 35 months, respectively. 14 weeks post-treatment initiation, rates of remission in Q8W>Q4W maintenance were 49% (bio-naïve) and 42% (bio-experienced), and in Q8W maintenance were 72% (bio-naïve) and 70% (bio-experienced) (Table 1). Among patients in Q8W>Q4W maintenance not in remission when dose escalating, 40% achieved clinical remission 3 months after dose escalation. These patients were older at treatment initiation (49 vs. 41 years, p=0.043) and had longer disease duration (6 vs. 3 years, p=0.029) than those who did not achieve remission. In Q8W>Q4W maintenance, 12- and 24-month treatment persistence after initiation was 83% and 48% (bio-naïve) and 79% and 51% (bio-experienced), respectively. After dose escalation, 12- and 24-month treatment persistence was 48% and 39% (bio-naïve) and 53% and 45% (bio-experienced).

Conclusion

Patients with UC who underwent VDZ Q8W>Q4W dose escalation achieved lower rates of remission than those remaining on Q8W, regardless of prior bio-experience. Age at treatment initiation and disease duration were significantly associated with remission among those who escalated to Q4W.

Disclosure

JFL: AbbVie, BMS, Janssen, Frenesius-Kabi, Pfizer, Sandoz, Takeda.
EJB: Participation in advisory boards or speaker services: Abbvie, Janssen, Takeda, Pfizer, Merck, Amgen, Pendopharm, Jamp, Fresenius, Kabi, Bausch Health, Celltrion, Eli Lilly, BMS, Grant/Research: Janssen, Abbvie, Any other investment or relationship that could be judged by a reasonable and knowledgeable participant to have the potential to influence the content of the training activity, Abbvie, Janssen, Takeda, Pfizer, Merck, Amgen, Pendopharm, Jamp, Fresenius, Kabi, Bausch Health, Celltrion, BMS.
AHS: Advisory Board Membership/Consultant: Abbvie, Amgen, BioJAMP, BMS, Celltrion, Fresenius Kabi, Janssen, McKesson, Mylan Pharmaceuticals, Organon, Pendopharm, Roche, Pfizer, Sandoz, Takeda, Viatris, Speakers’ Bureau: Abbvie, Amgen, Ferring, Fresenius Kabi, Janssen, Organon, Pfizer, Sandoz, Takeda, Research Grants: Abbvie, Arena, Celgene/BMS, Genentech, Janssen, Roche, Takeda.
PW: Personal fees from AbbVie, Ferring, Biogen, and Janssen
MJA, AW, RW: were employees of Takeda Canada Inc. at the time of the study.
RM, JW, CP: were employees of Pentavere Research Group Inc. at the time of the study.
LPB: Consulting from AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HACPharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio; grants from Takeda, Fresenius Kabi, and Celltrion; and lecture fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Lilly, Gilead, Viatris, and Medac.
BB: Advisor/Speaker: Ferring, Janssen, Abbvie, Takeda, Pfizer, BMS, Merck, Sandoz, Organon, Lifelabs, Celltrion. Advisor: Alimentiv, Gilead, Iterative Health, AMT, Celgene, Merck, Amgen, Pendopharm, Eli Lilly, BMS, Fresenius Kabi, Mylan, Viatris, Bausch Health, Celltrion Healthcare, BioJamp Pharma, Eupraxia. Research support: Janssen, Abbvie, GSK, BMS, Amgen, Genentech, Merck. Stock Options: Qu Biologic.