Risk factors for unclear margin in cold snare polypectomy for colorectal polyp.

OBJECTIVES: Cold snare polypectomy (CSP) is a common, simple, and safe procedure; however, it has a high rate of unclear margins. We analyzed the risk factors for unclear margins of colorectal polyp. METHODS: We retrospectively investigated colorectal polyps treated with CSP between July 2021 and July 2022, excluding those that could not be retrieved or pathologically nonneoplastic and hyperplastic polyps without margin evaluation. The clinicopathological features and risk factors for unclear margins were analyzed. Furthermore, the polyps were divided into two groups: those resected by experts and those resected by trainees. A 1 : 1 propensity score matching was performed. After matching, the risk factors for unclear margins in each group were analyzed as secondary outcomes. RESULTS: We analyzed 237 patients with 572 polyps; the margins were negative in 58.6% (negative group) and unclear in 41.4% (unclear group). The unclear margin was significantly higher at straddling folds (P = 0.0001), flexure points (P = 0.005), and in the procedures performed by trainees (P < 0.0001). Altogether, 198 propensity score matched pairs were explored for secondary outcomes. There were no significant differences in risk factors for unclear margins in the expert group, while in the trainee group, the unclear margin was significantly higher at the straddling folds (P = 0.0004) and flexure points (P = 0.005). CONCLUSIONS: We demonstrated that straddling folds, flexure points, and procedures performed by the trainees were significant risk factors for unclear margins, and we hypothesized that the rate of unclear margins will reduce as the trainees accumulate experience at difficult sites.

Using a Quality Management System and Risk-based Approach in Observational Studies to Obtain Robust Real-World Evidence.

The results of observational studies using real-world data, known as real-world evidence, have gradually started to be used in drug development and decision-making by policymakers. A good quality management system-a comprehensive system of process, data, and documentation to ensure quality-is important in obtaining real-world evidence. A risk-based approach is a common quality management system used in interventional studies. We used a quality management system and risk-based approach in an observational study on a designated intractable disease. Our multidisciplinary team assessed the risks of the real-world data study comprehensively and systematically. When using real-world data and evidence to support regulatory decisions, both the quality of the database and the validity of the outcome are important. We followed the seven steps of the risk-based approach for both database selection and research planning. We scored the risk of two candidate databases and chose the Japanese National Database of designated intractable diseases for this study. We also conducted a quantitative assessment of risks associated with research planning. After prioritizing the risks, we revised the research plan and outcomes to reflect the risk-based approach. We concluded that implementing a risk-based approach is feasible for an observational study using real-world data. Evaluating both database selection and research planning is important. A risk-based approach can be essential to obtain robust real-world evidence.

Palliative use of self-expanding metal stents in initially anticancer treatment-intolerant patients with esophageal cancer.

BACKGROUND: The post-insertion clinical course of esophageal self-expandable metal stents (SEMS) in initially frail patients with esophageal carcinoma (EC) with dysphagia remains unclear. This study aimed to assess dysphagia improvement and evaluate prognosis in initially frail patients with advanced EC following SEMS insertion. METHODS: We retrospectively reviewed EC patients with EC who underwent esophageal SEMS insertion at our institution between January 2014 and March 2023. Inclusion criteria comprised Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3 or ECOG PS 2 for individuals aged ≥ 75 years and recommendation for best supportive care by a multidisciplinary team. RESULTS: Forty-six patients met the inclusion criteria. Among them, 37 patients (80.4%) were ≥ 75 years old, and 21 patients (45.7%) exhibited ECOG PS 3 or 4. Dysphagia score (DS) ≥ 3 was observed in 27 patients (58.7%). All esophageal SEMS insertions were successfully completed. Post-procedure, there were two fatal cases of aspiration pneumonia and one perforation incident. DS improved to ≤ 1 in 25 patients (54.3%), with multivariate analysis indicating DS 3-4 and Glasgow Prognostic Score (GPS) 1-2 as negative predictive factors. The median overall survival was 4.1 months (95% confidence interval 1.8-6.5). CONCLUSIONS: Esophageal SEMS insertion effectively alleviated dysphagia in initially frail EC patients, yet prognosis remained poor, with occurrences of some fatal adverse events. Careful selection of candidates for esophageal SEMS insertions is crucial in this demographic, particularly considering the challenges in improving dysphagia for patients with DS 3-4 and GPS 1-2.

Activation of STING in pancreatic cancer-associated fibroblasts exerts an antitumor effect by enhancing tumor immunity.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate; therefore, the development of effective treatments is a priority. The stimulator of interferon genes (STING) pathway enhances tumor immunity by inducing the production of type 1 interferon (IFN) and proinflammatory cytokines and chemokines and promoting the infiltration of cytotoxic T cells. To assess the function of STING on pancreatic tumorigenesis, Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP mice (KPC mice) and Ptf1aER-Cre/+ LSL-KrasG12D/+ p53loxP/loxP/STING-/- mice (KPCS mice) were generated. However, STING deletion did not affect pancreatic tumorigenesis in mice. Because STING is expressed not only in immune cells but also in cancer-associated fibroblasts (CAFs), we evaluated the STING function in PDAC CAFs. A mouse STING agonist 5,6-Dimethyl-9-oxo-9H-xanthene-4-acetic acid (DMXAA) was administered to KPC mice and CAFs from KPC mice and the resulting immune response was evaluated. DMXAA activated STING in PDAC CAFs in KPC mice, promoting cytotoxic T cell infiltration by secreting proinflammatory cytokines and enhancing tumor immunity. We next generated STING-deficient PDAC cells and subcutaneous tumors in which STING was expressed only in CAFs by performing bone marrow transplantation and assessed the antitumor effect of STING-activated CAFs. The administration of DMXAA to subcutaneous tumors expressing STING only in CAFs sustained the antitumor effect of DMXAA. About half of human PDACs lacked STING expression in the cancer stroma, suggesting that STING activation in PDAC CAFs exerts an antitumor effect, and STING agonists can be more effective in tumors with high than in those with low STING expression in the stroma.

Clinical significance of circulating biomarkers of immune-checkpoint molecules with atezolizumab plus bevacizumab therapy in unresectable hepatocellular carcinoma.

BACKGROUND: The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC). METHOD: We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay. RESULTS: More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors. CONCLUSION: Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.

Construction of a nomogram combining CEUS and MRI imaging for preoperative diagnosis of microvascular invasion in hepatocellular carcinoma.

Purpose: To use Sonazoid contrast-enhanced ultrasound (S-CEUS) and Gadolinium-Ethoxybenzyl-Diethylenetriamine Penta-Acetic Acid magnetic-resonance imaging (EOB-MRI), exploring a non-invasive preoperative diagnostic strategy for microvascular invasion (MVI) of hepatocellular carcinoma (HCC). Methods: 111 newly developed HCC cases were retrospectively collected. Both S-CEUS and EOB-MRI examinations were performed within one month of hepatectomy. The following indicators were investigated: size; vascularity in three phases of S-CEUS; margin, signal intensity, and peritumoral wedge shape in EOB-MRI; tumoral homogeneity, presence and integrity of the tumoral capsule in S-CEUS or EOB-MRI; presence of branching enhancement in S-CEUS; baseline clinical and serological data. The least absolute shrinkage and selection operator regression and multivariate logistic regression analysis were applied to optimize feature selection for the model. A nomogram for MVI was developed and verified by bootstrap resampling. Results: Of the 16 variables we included, wedge and margin in HBP of EOB-MRI, capsule integrity in AP or HBP/PVP images of EOB-MRI/S-CEUS, and branching enhancement in AP of S-CEUS were identified as independent risk factors for MVI and incorporated into construction of the nomogram. The nomogram achieved an excellent diagnostic efficiency with an area under the curve of 0.8434 for full data training set and 0.7925 for bootstrapping validation set for 500 repetitions. In evaluating the nomogram, Hosmer-Lemeshow test for training set exhibited a good model fit with P > 0.05. Decision curve analysis of nomogram model yielded excellent clinical net benefit with a wide range (5-80 % and 85-94 %) of risk threshold. Conclusions: The MVI Nomogram established in this study may provide a strategy for optimizing the preoperative diagnosis of MVI, which in turn may improve the treatment and prognosis of MVI-related HCC.

A Novel Characteristic Gastric Mucus Named "Web-like Mucus" Potentially Induced by Vonoprazan.

Background: In the absence of Helicobacter pylori (HP) infection, a characteristic gastric mucus adhesion may appear during the use of vonoprazan. We named this novel characteristic mucus "web-like mucus" (WLM). This study aimed to determine the incidence and risk factors for WLM. Methods: Between January 2017 and January 2022, 5665 patients were enrolled in this study. The patients were divided into a proton-pump inhibitor (PPI)-prescribed group (n = 2000), a vonoprazan-prescribed group (n = 268), and a no-PPI/vonoprazan-prescribed (n = 3397) group, and the presence of WLM was examined. After excluding four patients with autoimmune gastritis, the remaining 264 patients in the vonoprazan group were divided into WLM and non-WLM groups, and their clinical features were analyzed. Results: A total of 55 (21%) patients had WLM, all in the vonoprazan-prescribed group. There were no significant differences in factors such as, sex, age, chronic kidney disease, diabetes mellitus, HP eradication history, smoking, or alcohol consumption between the WLM and non-WLM groups. The median duration from the start of vonoprazan administration to the endoscopic detection of WLM was 2 (1-24) months. Conclusions: WLM appears to be a characteristic feature in patients treated with vonoprazan.

Intestinal ultrasound for intestinal Behçet disease reflects endoscopic activity and histopathological findings.

BACKGROUND/AIMS: Intestinal Behçet disease is typically associated with ileocecal punched-out ulcers and significant morbidity and mortality. Intestinal ultrasound is a noninvasive imaging technique for disease monitoring. However, no previous reports have compared intestinal ultrasound with endoscopic ulcer activity or histopathological findings for intestinal Behçet disease. We evaluated the usefulness of intestinal ultrasound for assessing the activity of ileocecal ulcers in intestinal Behçet disease. METHODS: We retrospectively compared intestinal ultrasound findings with 73 corresponding endoscopic images and 6 resected specimens. The intestinal ultrasound findings were assessed for 7 parameters (bowel wall thickness, vascularity [evaluated using the modified Limberg score with color Doppler], bowel wall stratification, white-plaque sign [strong hyperechogenic lines or spots], mesenteric lymphadenopathy, extramural phlegmons, and fistulas), and endoscopic ulcer activity was classified into active, healing, and scar stages. Histopathological findings were evaluated by consensus among experienced pathologists. RESULTS: Bowel wall thickness (P< 0.001), vascularity (P< 0.001), loss of bowel wall stratification (P= 0.015), and white-plague sign (P= 0.013) were significantly exacerbated in the endoscopic active ulcer stage. Receiver operating characteristic curve analysis revealed that a bowel wall thickness of > 5.5 mm (sensitivity 89.7%, specificity 85.3%) was potentially useful for detecting active lesions. When compared with histopathological findings, an increase in bowel wall thickness reflected the ulcer marginal ridge, and the white-plaque sign reflected the ulcer bottom. CONCLUSIONS: Intestinal ultrasound is useful for monitoring intestinal ulcer activity in intestinal Behçet disease.

Single-Arm, Prospective, Interventional Study of Helicobacter pylori Eradication Rescue Therapy with Rifabutin, Metronidazole, and Vonoprazan.

Background and Objective: Rescue Helicobacter pylori eradication can be challenging. Rifabutin (RBT) demonstrates high activity against Helicobacter pylori and is incorporated into various rescue eradication regimens. This exploratory study was performed to evaluate the efficacy and safety of a rescue regimen comprising RBT, metronidazole (MNZ), and vonoprazan (VPZ). Methods: This prospective, single-center, single-arm, interventional study was performed in Japan. Eligible patients were those who underwent failed primary eradication treatment (7-day treatment with three drugs: VPZ or a proton pump inhibitor [PPI], amoxicillin [AMPC], and clarithromycin) and secondary eradication treatment (7-day treatment with three drugs: VPZ or a PPI, AMPC, and MNZ) and those who were unable to receive first- and second-line therapy because of penicillin allergy. Twenty Helicobacter pylori-positive patients were treated with RBT (150 mg twice daily), MNZ (250 mg twice daily), and VPZ (20 mg twice daily) for 10 days (RBT-MNZ-VPZ therapy). Eradication success was evaluated using the urea breath test. Drug susceptibility test results were available in 16 patients. This study is registered in the Japan Registry of Clinical Trials (jRCT031220504). Results: The intention-to-treat (ITT) and per-protocol (PP) eradication rates of RBT-MNZ-VPZ therapy were 70% (90% confidence interval [CI]: 49.2%-86.0%) and 72.2% (95% CI: 50.2%-88.4%), respectively. In the MNZ-susceptible subgroup, the ITT (n = 8) and PP (n = 7) eradication rates were 100% (90% CI: 68.8%-100%) and 100% (90% CI: 65.2%-100%). In the MNZ-resistant subgroup, the ITT (n = 8) and PP (n = 7) eradication rates were both 62.5% (90% CI: 28.9%-88.9%). All infections were RBT-susceptible. Conclusions: These findings suggest that RBT-MNZ-VPZ therapy may be a promising rescue regimen, especially in MNZ- and RBT-susceptible infections or patients with penicillin allergy.

Lenvatinib radiofrequency ablation sequential therapy offers survival benefits for patients with unresectable hepatocellular carcinoma at intermediate stage and the liver reserve of Child-Pugh A category: A multicenter study.

AIM: This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients. METHODS: One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child-Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy. RESULTS: After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin-bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186-0.782), 2.220 (95% CI, 1.410-3.493), and 0.982 (95% CI, 0.966-0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176-0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215-0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p < 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed. CONCLUSION: Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.

Complete response induced by nivolumab monotherapy in gastric neuroendocrine carcinoma: a case report.

No standard treatment has been established for gastric neuroendocrine carcinoma (G-NEC). We present the case of a patient with recurrent G-NEC who achieved a complete response (CR) with nivolumab. A woman in her 70 s, with no significant medical or family history of illness, underwent an upper gastrointestinal endoscopy, which revealed a Borrmann type 2 tumor in the gastric antrum. Malignant tumor cells were not detected in the endoscopic biopsy samples; however, a malignant gastric tumor was strongly suspected. Therefore, surgical resection was performed, and the tumor was pathologically diagnosed as a G-NEC with liver metastases. Adjuvant etoposide plus carboplatin was administered for four cycles, but recurrence in the liver was observed 5 months after the completion of adjuvant chemotherapy. Ramucirumab plus paclitaxel and irinotecan were introduced as second and third-line treatments. After these treatments, the mesenteric lymph node metastases expanded. Tumor mutation burden (TMB) was low (five mutations/megabase), and microsatellite instability remained stable. However, programmed death-ligand 1 Combined Positive Score (CPS) was ≥ 5 in the resected sample. Therefore, nivolumab monotherapy was introduced as a fourth-line treatment. The mesenteric lymph node metastases exhibited swelling 3 weeks after the initiation of nivolumab; however, they rapidly shrank, and CR was later achieved. Treatment with nivolumab is currently ongoing for 12 months. This is the first report of nivolumab monotherapy in a patient with G-NEC who showed pseudo-progression. Even in TMB-low and microsatellite stable cases, nivolumab may be a viable option for patients with G-NEC.

Establishment of nomogram prediction model of contrast-enhanced ultrasound and Gd-EOB-DTPA-enhanced MRI for vessels encapsulating tumor clusters pattern of hepatocellular carcinoma.

To establish clinical prediction models of vessels encapsulating tumor clusters (VETC) pattern using preoperative contrast-enhanced ultrasound (CEUS) and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (EOB-MRI) in patients with hepatocellular carcinoma (HCC). A total of 111 resected HCC lesions from 101 patients were included. Preoperative imaging features of CEUS and EOB-MRI, postoperative recurrence, and survival information were collected from medical records. The best subset regression and multivariable Cox regression were used to select variables to establish the prediction model. The VETC-positive group had a statistically lower survival rate than the VETC-negative group. The selected variables were peritumoral enhancement in the arterial phase (AP), hepatobiliary phase (HBP) on EOB-MRI, intratumoral branching enhancement in the AP of CEUS, intratumoral hypoenhancement in the portal phase of CEUS, incomplete capsule, and tumor size. A nomogram was developed. High and low nomogram scores with a cutoff value of 168 points showed different recurrence-free survival rates and overall survival rates. The area under the curve (AUC) and accuracy were 0.804 and 0.820, respectively, indicating good discrimination. Decision curve analysis showed a good clinical net benefit (threshold probability > 5%), while the Hosmer-Lemeshow test yielded excellent calibration (P = 0.6759). The AUC of the nomogram model combining EOB-MRI and CEUS was higher than that of the models with EOB-MRI factors only (0.767) and CEUS factors only (0.7). The nomogram verified by bootstrapping showed AUC and calibration curves similar to those of the nomogram model. The Prediction model based on CEUS and EOB-MRI is effective for preoperative noninvasive diagnosis of VETC.