Introduction

Accurate prediction of lymph node metastasis (LNM) in submucosal invasive (T1) colorectal cancer (CRC) is essential for determining the need for additional surgery following endoscopic resection. Conventional histopathological assessments, however, are limited by interobserver variability. This study aimed to develop and externally validate a stacking-based artificial intelligence (AI) model integrating histopathological whole slide images (WSIs) and clinical parameters to predict the risk of LNM in T1 CRC.

Aims & Methods

This retrospective study included 1,056 patients with histologically confirmed T1 CRC treated at Showa Medical University Northern Yokohama Hospital. Of these, 593 cases were used for model training and 100 for internal testing. External validation was conducted on 25 cases from two independent institutions.
The proposed stacking ensemble model incorporated the Multiple Instance Self-Training (MIST) score derived from WSIs, patient sex, and tumor location (colon vs. rectum). Base learners included logistic regression, XGBoost, and random forest, with a meta-learner synthesizing their outputs to generate the final LNM prediction. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) in both internal and external cohorts.

Results

LNM was observed in 69 (11.6%) training cases, 15 (15.0%) test cases, and 2 (8.0%) external validation cases. The model achieved an AUC of 0.6965 in the internal test cohort and 0.7500 in the external validation cohort, demonstrating stable and generalizable predictive performance.
A representative case involved a 64-year-old man with a 16-mm type 0-Is lesion in the sigmoid colon resected via endoscopic mucosal resection (EMR). Histopathology showed well-differentiated tubular adenocarcinoma (tub1 > tub2), submucosal invasion depth of 3,300 µm (T1b), tumor budding grade BD1, Ly0, V1a, and negative resection margins (HM0, VM0). Despite guideline-based recommendations prompting additional surgical resection, no LNM was found (N0, 0/16), and the patient remained recurrence-free five years postoperatively—consistent with the AI model’s prediction.

Conclusion

The stacking-based AI model exhibited robust and generalizable performance in predicting LNM in T1 CRC, both internally and across external institutions. This approach offers a complementary tool to conventional pathology and may enhance individualized decision-making regarding the necessity of additional surgical intervention.

Clinical Case Summary

We present a case of a 66 year old woman that has been treated due to metastatic colorectal cancer. In 2021 right hemicolectomy was performed, but due to occurance of solitary liver methastasis in the left lobe SBRT was performed in September 2022. In January 2024 upper GI endoscopy was performed due to dysphagia and large 25 mm ulcer was seen in the distal esophagus. CT scan was normal, multiple biopsies were negative for malignancy it was concluded that it is a post-SBRT ulcer. In February 2024 she presented with acute pain in left thoracic cavity followed with breath shortness and low blood pressure. Inflammatory parameters were elevated (C-reactive protein 350, leucocytes 25 with high levels of troponin and D-dimers). Urgent CT scan was done and showed leakage of the contrast from the 15 mm perforation of distal esophagus to the pericard with pneumopericard but without pneumotorax or pneumomediastinum. We decided to perform combine minimally invasive closure techniques due to hemodynamic instability of the patient. Procedures were done in the cardiothoracic operation room with patient intubated and on dual vasopressor therapy. First pericardial drainage was performed to decompress the air and a small amount of fluid and pus from the pericard. Immediately after that we proceeded with the upper endoscopy and visualize the perforation of the distal esophagus with relative stenosis of the lumen the was still passable with the scope. A 10-cm fully covered esophageal stent was placed sucesfully and closed the perforation site. Postinterventional recovery was adequate without any significant complications. Seventh day after the procedure CT scan showed adequate stent postition without extralumination of the contrast to the pericard, after that pericardial drain was removed and patient stared with liquid and then mixed diet that was uneventfull and was discharged 14 days after the intervention. Unfortunatelly patient died 9 months ​later due to disease progression.

References

Additional high quality radiology pictures will be presented

Introduction

Acute pancreatitis (AP) is a systemic inflammatory disease with a rising incidence and high mortality, particularly in severe cases. Cardiac abnormalities, including heart failure and arrhythmias, are frequently observed during and after AP-related hospitalizations. Despite the known association between AP and cardiac complications, the bidirectional relationship between cardiac changes and AP outcomes remains poorly understood.

Aims & Methods

This study aims to systematically review and meta-analyze the bidirectional associations between cardiac abnormalities and AP outcomes, focusing on mortality, severity, and post-discharge complications. A systematic search was conducted on November 5, 2023, across MEDLINE, Embase, and Cochrane CENTRAL, with additional backward and forward citation searches completed on February 19, 2024. The study protocol was registered on PROSPERO (CRD42023479679, CRD42023479674). Observational studies and randomized controlled trials (RCTs) assessing cardiac abnormalities in AP patients, including atrial fibrillation (AF), repolarization changes, and QTc prolongation, were included. Data on mortality and AP severity were analyzed using odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI) in a random-effects model. The PRISMA 2020 guideline and Cochrane Handbook were followed for study selection and data extraction. The risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool.

Results

Thirty-two studies involving 5.3 million patients were included, with 1.3 million AP patients analyzed for specific cardiac abnormalities. Patients with AF had nearly threefold higher odds of in-hospital mortality compared to those without AF (OR: 2.69; CI: 1.34–5.38). Severe and moderately severe AP [(M)SAP] tripled the odds of ECG repolarization changes compared to mild AP (OR: 2.75; CI: 1.19–6.36). No significant association was found between (M)SAP and QTc prolongation (OR: 2.25; CI: 0.63–8.03). Pre-existing chronic heart failure (CHF) was associated with a threefold increased odds of mortality (OR: 3.43; CI: 1.96–5.98). According to the systematic review, although data were limited, echocardiographic parameters, such as pericardial effusion and cardiac dysfunction, were associated with worse AP outcomes. Elevated cardiac laboratory markers, including creatine kinase-MB (CK-MB), were associated with higher mortality and longer hospital stays.

Conclusion

This study highlights the significant bidirectional relationship between cardiac abnormalities and AP outcomes. Patients with AF face a 2.7-fold increased odds of in-hospital mortality, while those with pre-existing CHF have a 3.4-fold higher odds of mortality in AP. Additionally, (M)SAP is associated with three times higher odds of ECG repolarization changes compared to mild AP. These findings underscore the importance of routine cardiology screening in AP patients during hospitalization. Future research should focus on longitudinal studies to better understand the long-term cardiovascular complications following AP and to develop targeted interventions to reduce mortality and improve outcomes. Implementing early cardiac assessment and monitoring in AP patients, particularly those with pre-existing cardiac conditions, could significantly improve clinical management and reduce mortality rates.

Introduction

Endoscopic papillectomy (EP) is indicated for papillary adenoma that do not extend into the pancreatic bile duct. There are cases in which en bloc resection or curative resection is expected to be difficult with conventional EP. For such cases, we introduced hybrid EP, in which snaring is performed after peri-lesion incision using a dedicated ESD knife.

Aims & Methods

A total of 13 cases who underwent hybrid EP between 2022 and 2024 were identified from our prospectively maintained database. Hybrid EP involved a circumferential incision with partial submucosal dissection, and subsequent snare resection of ampullary tumors, which was performed by two endoscopists with expertise in ESD or endoscopic retrograde cholangiopancreatography. Demographic data and clinicopathological outcomes were retrospectively evaluated.

Results

En bloc resection was achieved by hybrid EP in all 13cases, with the median procedure time of 118 (range: 65-170) minutes. The median diameters of the resected specimens and tumors were 25 and 15 mm, respectively. All lateral margins were clear, whereas vertical margin was uncertain in one (7.6%), resulting in the complete resection rate of 92.4%. Postoperative bleeding developed in two (15.3%). No tumor recurrence was observed even in that case with uncertain vertical margin, after a median follow-up of 244 (range, 97-678) days.

Conclusion

Hybrid EP is an useful technique for duodenal papillary tumors that are difficult to resect en bloc or curatively by conventional EP.
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Introduction

Sarcopenia is characterized by loss of skeletal muscle mass and strength, and commonly observed in patients with chronic liver disease (CLD). However, simple and practical assessment tools for consideration of early intervention in patients with risk of progression of muscle abnormalities remain limited, as muscle volume assessment requires specialized expensive equipment not generally used by a family physician, e.g., computed tomography (CT) or bioelectrical impedance analysis.

Aims & Methods

Using the Geriatric Nutritional Risk Index (GNRI), calculated based only on body weight, height, and serum albumin (AJCN 2005), the present study aimed to examine a novel scoring system used to assess risk of sarcopenia and muscle abnormality development in CLD patients.
This retrospective analysis was conducted using medical records of 1063 Japanese CLD patients (median age 70 years; male:female = 676:387; HCV:HBV:HBV and HCV:alcohol:others = 573:146:4:127:213; Child-Pugh A:B:C = 927:115:21; hepatocellular carcinoma history or complication = 300) who underwent related examinations from 2015 to 2024. Muscle area at the middle of the L3 level shown by CT was evaluated using a 3D image analysis system, with the value for skeletal muscle index (SMI), determined based on muscle area (cm²), calculated using the mean value for L3 level/height (m²). Muscle volume loss (MVL) and handgrip strength decline (HGSD) were assessed according to the Japan Society of Hepatology criteria (SMI and HGSD cutoff values for male/female; 42/38 cm²/m² and 28/18 kg, respectively). Logistic regression analysis was then used to identify predictive factors for sarcopenia. Finally, a risk scoring system was developed based on the odds ratio (OR) values for significant factors.

Results

There were 145 patients (13.6%) with sarcopenia, 226 (21.3%) with HGSD, and 149 (14.0%) with MVL, with an abnormal GNRI status noted in 333 (31.3%). A scoring system was developed based on five predictive factors; abnormal GNRI (<98) (OR 4.88), elderly (65-74 years, OR 2.67), late-stage elderly (≥75 years, OR 6.09), female (OR 2.11), and advanced hepatocellular carcinoma (HCC) (TNM stage IV, OR 2.61), which remained following multivariate analysis. Points were assigned based on OR value, with1 point for OR ≤3 and 2 points for OR ≥4. The rate of prevalence of sarcopenia, HGSD, and MVL showed a significant increase with a higher score, with those conditions seen in 2.4%, 13.8%, and 6.9%, respectively, of patients with low risk (0/1 points), 9.0%, 23.7%, and 19.8%, respectively, of those with moderate risk (2 points), 22.0%, 29.0%, and 18.8%, respectively, of those with high risk (3 points), and 38.8%, 27.5%, and 16.9%, respectively, of those with very high/super-high risk (4/5/6 points) (p<0.001). Additionally, GNRI cutoff values for HGSD and MVL were 101.5 (AUC 0.670) and 97.5 (AUC 0.749), respectively, approximating the abnormal GNRI cutoff value of 98.

Conclusion

This GNRI-based scoring system is likely to be a simple, cost-effective tool that does not require any special equipment when assessing the risk of sarcopenia or muscle abnormalities. It may also be used in clinical practice as a method of identifying patients who require early intervention.

Introduction

Colorectal cancer (CRC) therapy faces significant challenges, including drug resistance, tumour heterogeneity, metastatic progression, and treatment-associated toxicity. CRC and other cancers exhibit increased levels of Fe(II) due to dysregulated iron metabolism, which can act as a trigger for selective prodrug activation. In this study, we explore the therapeutic potential of a novel tumour-activated prodrug platform based on 1,2,4,5-tetraoxane scaffold that is selectively activated in cancer cells with high levels of labile Fe(II). As a proof-of-concept, we evaluated the therapeutic potential of 5b, a prodrug coupled with doxorubicin (DOX), which releases this cytotoxic payload upon activation by the labile Fe(II) pool in the cytoplasm of cancer cells.

Aims & Methods

The therapeutic potential and mechanism of action of 5b was evaluated both in vitro and in vivo. IC₅₀ values were determined across multiple cancer cell lines and compared to non-tumorigenic cells. To confirm iron-dependency, HCT116 cell viability was assessed upon co-incubation with 5b and iron chelator deferoxamine (DFO). Co-incubation with apoptosis inhibitor Z-VAD-FMK (Zvad) or ferroptosis inhibitor liproxstatin-1 was used to assess cell death mechanism. The sub-cellular location of 5b activation was evaluated by fluorescence microscopy. In vivo efficacy was evaluated in a xenograft mouse model using immunocompromised mice implanted with HT29 cells and intraperitoneal administrations of 5b, assessing tumour burden and systemic toxicity.

Results

Prodrug 5b effectively reduced cell viability in CRC cells HCT116 and HT29, as well as in glioblastoma (U251), prostate cancer (PC3) and breast cancer (MCF7) cells, with IC₅₀ values ranging from 1.64 to 6.69 µM. Notably, 5b was over 2000 times less toxic than DOX in non-tumorigenic cells AML12 (5b IC₅₀ = 398.2 µM vs. DOX IC₅₀ = 0.18 µM). Taking advantage of DOX intrinsic fluorescence properties (while 5b pro-drug is non-fluorescent), we used fluorescence microscopy analysis to confirm that 5b released its fluorescent DOX payload in the cytoplasm, after activation by labile Fe(II). The significant decrease in cell viability induced by 5b (p < 0.0001) was rescued by the iron chelator DFO and by the ferroptosis inhibitor liproxstatin-1 (p < 0.01) but not by pan-caspase inhibitor Zvad, suggesting that ferroptosis may be the primary mechanism of cell death. In vivo, 5b significantly reduced the relative tumour volume (p < 0.05), demonstrating greater efficacy than DOX, with only minor cardiotoxicity side-effects (multifocal loci of fibrosis affecting of 0.2% of left ventricle volume).

Conclusion

Prodrug 5b efficiently released its DOX payload in response to the cytoplasmatic labile Fe(II), effectively reducing cancer cell viability both in vitro and in vivo, while demonstrating significantly lower toxicity compared to DOX itself. Given its Fe(II)-dependent activation, 5b represents a promising strategy to exploit cancer cell iron addiction for cancer therapy. Future work should further validate ferroptosis as cell death mechanism, optimize the selection of cytotoxic payloads for tumours with dysregulated iron metabolism, and assess its efficacy in relation to KRAS mutational status. Funding: CMPR: PTDC/MED-FAR/3492/2021, LCF/PR/HR21/52410028; RM: 2022.07857.PTDC, PTDC/MED-QUI/30021/2017; VM: 10.54499/2023.11531.PEX; DMS: LCF/TR/CI22/52660003

Disclosure

The authors declare that this work is associated with intellectual property protection under the following patents/patent requests:
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “1,2,4,5-tetraoxane compounds, a drug delivery system based in said compounds useful in diagnoses and therapy, and methods thereof”, Portuguese Patent Application nº PT117644 from 16-12-2021;
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “Drug delivery systems based on endoperoxides useful in diagnosis and therapy, and methods thereof”, PCT Application nº PCT/IB2022/062107 from 13-12-2022;
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “Drug delivery systems based on endoperoxides useful in diagnosis and therapy, and methods thereof”, European Patent Office Application nº EP4448107 from 23-10-2024;
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “Drug delivery systems based on endoperoxides useful in diagnosis and therapy, and methods thereof”, United States Patent and Trademark Office patent application nº US20250064840 from 27-02-2025.

Clinical Case Summary

A 69-year-old male presented with dysphagia, food regurgitation, weight loss, and halitosis with a 12-month evolution. An upper endoscopy revealed, at 32 cm from the dental arch, a large food bolus impacted in an area consistent with a large esophageal diverticulum (Figure 1), along with isolated esophageal contractions suggestive of tertiary contractions. A barium swallow study confirmed a distal esophageal diverticulum measuring 6x5 cm (Figure 2). Subsequently, a chest CT scan showed the diverticulum with a large amount of food content inside (Figure 3). High-resolution esophageal manometry (HRM) demonstrated a hypercontractile pattern of the esophageal body in more than 20% of swallows, consistent with a diagnosis of hypercontractile esophagus or Jackhammer esophagus (Figures 4 and 5). Due to the symptoms and the size of the diverticulum, thoracoscopic diverticulectomy was performed, with favorable outcomes.
Esophageal diverticulum are uncommon, with a reported prevalence of 0.06% to 4%. In the case of hypercontractile esophagus, a pulsion mechanism is involved, with mucosal and submucosal protrusion secondary to increased intraesophageal pressure. HRM is useful for diagnosing underlying and triggering motility disorders, as well as guiding therapeutic decisions. Management should be individualized and may range from peroral endoscopic myotomy (POEM) to laparoscopic or open surgery.

References

Figure 1. Endoscopic view of the esophageal diverticulum. A: esophageal lumen. B: diverticular lumen with food bolus inside.

Figure 2. Barium swallow study showing an epiphrenic esophageal diverticulum with a 1 cm diverticular neck.

Figure 3. Chest computed tomography showing a large esophageal diverticulum with food content and an air-fluid level. A: sagittal view. B: axial view.

Figure 4. High-resolution manometry: hypercontractile contraction pattern (Distal Contractile Integral -DCI- >8000 mmHg·s·cm). Horizontal notch in the wave contour (arrow) corresponding to the diverticular neck.

Figure 5. Image of the resected diverticulum compared with a standard surgical scissor (18 cm long).