CXCR4-Targeted Macrophage-Derived Biomimetic Hybrid Vesicle Nanoplatform for Enhanced Cancer Therapy through Codelivery of Manganese and Doxorubicin.

Immune-cell-derived membranes have garnered significant attention as innovative delivery modalities in cancer immunotherapy for their intrinsic immune-modulating functionalities and superior biocompatibilities. Integrating additional parental cell membranes or synthetic lipid vesicles into cellular vesicles can further potentiate their capacities to perform combinatorial pharmacological activities in activating antitumor immunity, thus providing insights into the potential of hybrid cellular vesicles as versatile delivery vehicles for cancer immunotherapy. Here, we have developed a macrophage-membrane-derived hybrid vesicle that has the dual functions of transporting immunotherapeutic drugs and shaping the polarization of tumor-associated macrophages for cancer immunotherapy. The platform combines M1 macrophage-membrane-derived vesicles with CXCR4-binding-peptide-conjugated liposomes loaded with manganese and doxorubicin. The hybrid nanovesicles exhibited remarkable macrophage-targeting capacity through the CXCR4-binding peptide, resulting in enhanced macrophage polarization to the antitumoral M1 phenotype characterized by proinflammatory cytokine release. The manganese/doxorubicin-loaded hybrid vesicles in the CXCR4-expressing tumor cells evoked potent cancer cytotoxicity, immunogenic cell death of tumor cells, and STING activation. Moreover, cotreatment with manganese and doxorubicin promoted dendritic cell maturation, enabling effective tumor growth inhibition. In murine models of CT26 colon carcinoma and 4T1 breast cancer, intravenous administration of the manganese/doxorubicin-loaded hybrid vesicles elicited robust tumor-suppressing activity at a low dosage without adverse systemic effects. Local administration of hybrid nanovesicles also induced an abscessive effect in a bilateral 4T1 tumor model. This study demonstrates a promising biomimetic manganese/doxorubicin-based hybrid nanovesicle platform for effective cancer immunotherapy tailored to the tumor microenvironment, which may offer an innovative approach to combinatorial immunotherapy.

Pathogenesis and biomarkers of colorectal cancer by epigenetic alteration.

Colorectal cancer (CRC) ranks third in cancer incidence and stands as the second leading cause of cancer-related deaths globally. CRC tumorigenesis results from a cumulative set of genetic and epigenetic alterations, disrupting cancer-regulatory processes like cell proliferation, metabolism, angiogenesis, cell death, invasion, and metastasis. Key epigenetic modifications observed in cancers encompass abnormal DNA methylation, atypical histone modifications, and irregularities in noncoding RNAs, such as microRNAs and long noncoding RNAs. The advancement in genomic technologies has positioned these genetic and epigenetic shifts as potential clinical biomarkers for CRC patients. This review concisely covers the fundamental principles of CRC-associated epigenetic changes, and examines in detail their emerging role as biomarkers for early detection, prognosis, and treatment response prediction.

The Effect of Intervention for Improving Colonoscopy Quality Is Associated with the Personality Traits of Endoscopists.

Background/Aims: This study investigated whether the personality traits of endoscopists are associated with the effect of interventions for the improvement of colonoscopy quality. Methods: This prospective, multicenter, single-blind study was performed with 13 endoscopists in three health screening centers over a 12-month period. Quality indicators (QIs), including adenoma detection rate (ADR), polyp detection rate (PDR), and withdrawal time, were measured every 3 months. Consecutive interventions for the improvement of colonoscopy quality were conducted every 3 months, which included the personal notification of QIs, the in-group notification of QIs, and finally a targeted "quality education" session. The personality traits of each endoscopist were evaluated for perfectionism, fear of negative evaluation, and cognitive flexibility after the last QI assessment. Results: A total of 4,095 colonoscopies were evaluated to measure the QIs of the individual endoscopists for 12 months. The mean ADR, PDR, and withdrawal time of the 13 endoscopists were 32.3%, 47.7%, and 394 seconds at baseline and increased to 39.0%, 55.1%, and 430 seconds by the end of the study (p=0.003, p=0.006, and p=0.004, respectively). Among the three interventions, only quality education significantly improved QIs: ADR, 36.0% to 39.0% (odds ratio, 1.28; 95% confidence interval, 1.01 to 1.63). The improvement of ADR and PDR by education was significantly associated with perfectionism (r=0.617, p=0.033 and r=0.635, p=0.027, respectively) and fear of negative evaluation (r=0.704, p=0.011 and r=0.761, p=0.004, respectively). Conclusions: Education can improve colonoscopy quality, and its effect size is associated with an endoscopist's personal traits such as perfectionism and fear of negative evaluation (Clinical-Trials.gov Registry NCT03796169).

Deep learning in negative small-bowel capsule endoscopy improves small-bowel lesion detection and diagnostic yield.

OBJECTIVES: Although several studies have shown the usefulness of artificial intelligence to identify abnormalities in small-bowel capsule endoscopy (SBCE) images, few studies have proven its actual clinical usefulness. Thus, the aim of this study was to examine whether meaningful findings could be obtained when negative SBCE videos were reanalyzed with a deep convolutional neural network (CNN) model. METHODS: Clinical data of patients who received SBCE for suspected small-bowel bleeding at two academic hospitals between February 2018 and July 2020 were retrospectively collected. All SBCE videos read as negative were reanalyzed with the CNN algorithm developed in our previous study. Meaningful findings such as angioectasias and ulcers were finally decided after reviewing CNN-selected images by two gastroenterologists. RESULTS: Among 202 SBCE videos, 103 (51.0%) were read as negative by humans. Meaningful findings were detected in 63 (61.2%) of these 103 videos after reanalyzing them with the CNN model. There were 79 red spots or angioectasias in 40 videos and 66 erosions or ulcers in 35 videos. After reanalysis, the diagnosis was changed for 10 (10.3%) patients who had initially negative SBCE results. During a mean follow-up of 16.5 months, rebleeding occurred in 19 (18.4%) patients. The rebleeding rate was 23.6% (13/55) for patients with meaningful findings and 16.1% (5/31) for patients without meaningful findings (P = 0.411). CONCLUSION: Our CNN algorithm detected meaningful findings in negative SBCE videos that were missed by humans. The use of deep CNN for SBCE image reading is expected to compensate for human error.

Metabolic bulk volume from FDG PET as an independent predictor of progression-free survival in follicular lymphoma.

Background: Total metabolic tumor volume (TMTV) in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) predicts patient outcome in follicular lymphoma (FL); however, it requires laborious segmentation of all lesions. We investigated the prognostic value of the metabolic bulk volume (MBV) obtained from the single largest lesion. Methods: Pretreatment FDG PET/computed tomography (CT) scans of 201 patients were analyzed for TMTV and MBV using a 41% maximum standardized uptake value (SUVmax) threshold. Results: During a median follow-up of 3.2 years, 54 events, including 14 deaths, occurred. Optimal cut-offs were 121.1 cm3 for TMTV and 24.8 cm3 for MBV. Univariable predictors of progression-free survival (PFS) included a high Follicular Lymphoma International Prognostic Index 2 (FLIPI2) score, TMTV, and MBV. In the multivariable analysis, high TMTV and MBV were independent predictors of worse PFS (P =0.015 and 0.033). Furthermore, in a sub-group with FLIP2 scores of 0-2 (n = 132), high MBV could identify patients with worse PFS (P = 0.007). . Conclusion: Readily measurable MBV is useful for stratifying risk in FL patients.

Semi-quantitative FDG parameters predict survival in multiple myeloma patients without autologous stem cell transplantation.

BACKGROUND: F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is useful in multiple myeloma (MM) for initial workup and treatment response evaluation. Herein, we evaluated the prognostic value of semi-quantitative FDG parameters for predicting the overall survival (OS) of MM patients with or without autologous stem cell transplantation (ASCT). METHODS: Study subjects comprised 227 MM patients who underwent baseline FDG PET/CT. Therein, 123 underwent ASCT while 104 did not. Volumes of interest (VOIs) of bones were drawn on CT images using a threshold of 150 Hounsfield units. FDG parameters of maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and number of focal lesions (FLs) were measured. Kaplan-Meier survival analysis with log-rank tests and Cox proportional hazards regression analyses were performed for overall survival (OS). RESULTS: In the ASCT cohort, R-ISS stage, MTV, and TLG were associated with survival. In the non-ASCT cohort, however, R-ISS stage was not associated with patient outcomes. In contrast, high SUVmax, SUVmean, MTV, TLG, and FL could predict worse OS (hazard ratio [HR] = 2.569, 2.649, 2.506, 2.839, and 1.988, respectively). Importantly, combining FDG parameters with R-ISS stage provided a new risk classification system that discriminated worse OS in the non-ASCT cohort significantly better than did R-ISS stage alone. CONCLUSIONS: In the non-ASCT cohort, semi-quantitative FDG parameters were significant predictors of worse OS. Furthermore, combining FDG parameters with R-ISS stage may provide a new risk staging system that can better stratify the survival of MM patients without ASCT.

Interobserver Variation of Bowel Preparation for Colonoscopy.

BACKGROUD/AIMS: Several bowel preparation scales have been developed, but they are variably validated to guide clinical practice. The aim of this study was to assess the interobserver reliability between internal and external endoscopists using the Harefield Cleaning Scale (HCS). METHODS: Data was collected from a study evaluating the efficacy of oral sulfate tablets in patients undergoing colonoscopy. The assessments of bowel cleansing were carried out by four internal endoscopists at the time of the procedure, and colonoscopy video recordings were reviewed independently by three external endoscopists. Interobserver reliability was quantified using Cohen's Kappa coefficient, and scores and grades of each segment were compared between internal and external endoscopist groups. RESULTS: Among 83 colonoscopy videos, interobserver reliability yielded a fair agreement between internal and external endoscopists, with a Cohen's Kappa coefficient of 0.39 (95% CI 0.08-0.70). Successful overall preparation rates (100% vs 98.8%) and high-quality preparation rates (88% vs 94%) were excellent and comparable between the two groups. In contrast, one case of unsuccessful cleansing (grade C) was documented, only in the external group. In addition, the interobserver reliability between internal and external endoscopists comparing each segmental score yielded a slight agreement in the descending colon (0.11, 95% CI - 0.02 to 0.23) and sigmoid colon (0.04, 95% CI - 0.18 to 0.26). DISCUSSION: Interobserver reliability between internal and external endoscopists using the HCS was fair. However, the HCS may be limited as a reliable scale for assessing bowel preparation quality in the left colon, where liquid is mainly retained in the left lateral position.

Effects of suprahyoid muscle strengthening exercise using kinesiology taping on muscle activation and thickness in community-dwelling elderly: A randomized controlled trial.

BACKGROUND: Recently, swallowing resistive exercise using kinesiology taping (KT) has been reported as a novel method for dysphagia rehabilitation However, clinical evidence is still unclear, and effects in the elderly have not been confirmed. OBJECTIVE: This study aimed to investigate the effects of suprahyoid muscle strengthening exercise using KT on muscle activation and thickness in community-dwelling elderly. METHODS: A total of 24 healthy older people were enrolled in this study and randomly assigned to an experimental group and a placebo group. In the experimental group, KT was attached to the front of the neck with a tension of about 70% to 80%, and a resistive swallowing exercise was performed. In the placebo group, the tape was applied similarly but without tension. Both groups performed resistive swallowing exercises 10 times a day (50 swallows per day) for 6 weeks. The activation and thickness of the suprahyoid muscles were measured using portable ultrasound equipment and an surface electromyelograph device. RESULTS: The experimental group showed a significant increase in suprahyoid muscle activation (mean and peak) and muscle thickness (digastric and mylohyoid) than the placebo group (all, P < .05). CONCLUSION: This study confirmed that suprahyoid muscle strengthening exercise using KT had a positive effect on the suprahyoid muscles in healthy older adults, thus suggesting the possibility of a therapeutic exercise method for dysphagia rehabilitation.

Rescue technique for self-expandable metallic stent placement using ultrathin endoscope after failure of the conventional method in patients with malignant colon obstruction: a multicenter retrospective study.

BACKGROUND AND AIMS: Self-expandable metallic stents (SEMS) can be used to treat malignant colorectal obstruction (MCO). Guidewire insertion to the proximal site of MCO is the most important step for SEMS placement. However, some patients cannot undergo guidewire insertion because of total obstruction or location at anatomically challenging areas. We report a guidewire insertion technique using an ultrathin endoscope (UTE) in patients with MCO in whom conventional SEMS insertion failed. METHODS: This study was a retrospective cohort study conducted at three academic centers in Korea. The medical records of 956 consecutive patients who underwent SEMS placement during 2012-2021 were analyzed. After failing guidewire insertion using a colonoscope, a UTE was inserted. Guidewire insertion was done through the working channel of the UTE. Following guidewire insertion, the endoscope was removed from the patient. While removing the endoscope, the guidewire was advanced to be located at the originally inserted site. Then, the colonoscope was inserted over the guidewire, and SEMS was replaced. RESULTS: Conventional SEMS insertion failed in 75 patients. Of these, guidewire insertion using a UTE was tried in 59 patients. The rate of technical success was 91.5% (54/59). Considering all patients, the overall technical success rate of SEMS placement was 97.8% (935/956). This technique increased the technical success rate by 5.6% among the total cohort. CONCLUSIONS: The UTE facilitated guidewire insertion and enhanced the overall success rate for SEMS placement. In addition, this technique can be used as a rescue method when guidewire insertion fails using a colonoscope.

Association between regular physical activity and lower incidence of colorectal cancer in patients with diabetes mellitus: a nationwide cohort study.

AIM: The aim of this work was to investigate the association between changes in physical activity (PA) status and the development of colorectal cancer (CRC) in patients with diabetes. METHOD: This nationwide population study included 1 439 152 patients with diabetes who underwent a health screening provided by the Korean National Health Insurance Service between January 2009 and December 2012 and a follow-up screening after 2 years. Based on changes in PA status, participants were categorized into four groups: remained inactive, remained active, active-to-inactive and inactive-to-active. RESULTS: During the median follow-up period of 5.2 years, 38 244 new cases of CRC were diagnosed. Compared with the remained inactive group, among the three other groups, the remained active group had the lowest risk of CRC [adjusted hazard ratio (aHR) 0.93; 95% CI 0.90-0.96], followed by the inactive-to-active group (aHR 0.97; 95% CI 0.94-1.00) and active-to-inactive group (aHR 0.99; 95% CI 0.96-1.02), after adjusting for confounding variables (p = 0.0007). This reduction in cancer incidence in the remained active group was observed for both rectal cancer (aHR 0.87, 95% CI 0.79-0.95) and colon cancer (aHR 0.93, 95% CI 0.90-0.97), irrespective of sex. In terms of the intensity and amount of PA, moderate intensity PA was the most effective, and a positive correlation was found between the amount of PA and the reduction in CRC incidence. CONCLUSION: Regular PA was independently associated with a decreased risk of CRC in patients with diabetes. The intensity and amount of physical activity both play a role in reducing the risk.

Diagnostic Value of FDG PET/CT in Surveillance after Curative Resection of Breast Cancer.

With increasing incidence of breast cancer and improvement in treatment, the concern about surveillance management also has increased. This retrospective study was designed to evaluate the diagnostic value of routine surveillance FDG PET/CT in patients with breast cancer. The diagnostic performance of surveillance PET/CT was analyzed regarding sensitivity, specificity, positive predictive value, negative predictive value and accuracy. The diagnostic accuracy was defined as the ability to differentiate recurrence and no-disease correctly and the proportion of true results, either true positive or true negative, in the population. Findings from pathologic examination; other imaging modalities such as CT, MRI and bone scan; or clinical follow-up were used as the reference standard. In this study of 1681 consecutive patients with breast cancer who underwent curative surgery, surveillance fluorodeoxyglucose PET/CT showed good diagnostic performance in the detection of clinically unexpected recurrent breast cancer or other malignancy, with a sensitivity of 100%, specificity of 98.5%, positive predictive value of 70.5%, negative predictive value of 100% and accuracy of 98.5%. In conclusion, surveillance fluorodeoxyglucose PET/CT showed good diagnostic performance in the detection of clinically unexpected recurrent breast cancer after curative surgery.

Cluster analysis of autoencoder-extracted FDG PET/CT features identifies multiple myeloma patients with poor prognosis.

F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a robust imaging modality used for staging multiple myeloma (MM) and assessing treatment responses. Herein, we extracted features from the FDG PET/CT images of MM patients using an artificial intelligence autoencoder algorithm that constructs a compressed representation of input data. We then evaluated the prognostic value of the image-feature clusters thus extracted. Conventional image parameters including metabolic tumor volume (MTV) were measured on volumes-of-interests (VOIs) covering only the bones. Features were extracted with the autoencoder algorithm on bone-covering VOIs. Supervised and unsupervised clustering were performed on image features. Survival analyses for progression-free survival (PFS) were performed for conventional parameters and clusters. In result, supervised and unsupervised clustering of the image features grouped the subjects into three clusters (A, B, and C). In multivariable Cox regression analysis, unsupervised cluster C, supervised cluster C, and high MTV were significant independent predictors of worse PFS. Supervised and unsupervised cluster analyses of image features extracted from FDG PET/CT scans of MM patients by an autoencoder allowed significant and independent prediction of worse PFS. Therefore, artificial intelligence algorithm-based cluster analyses of FDG PET/CT images could be useful for MM risk stratification.

Development and Validation of 18F-FDG PET/CT-Based Models for Predicting Successful Complete Cytoreduction During Primary Cytoreductive Surgery for Advanced Ovarian cancer.

PURPOSE: The aim of this study was to develop an 18F-FDG PET/CT-based model to predict complete cytoreduction during primary cytoreductive surgery (CRS) for ovarian cancer (OC). PATIENTS AND METHODS: We retrospectively identified patients with stage III-IV OC who underwent primary CRS between June 2013 and February 2020 at 2 tertiary centers. Patients from each hospital were assigned to training and test sets. The abdominal cavity was divided into 3 sections, and data for the PET/CT-derived parameters were collected through image analysis. Various prediction models were constructed by combining clinicopathologic characteristics and PET/CT-derived parameters. The performance of the model with the highest area under the receiver operating characteristic curve (AUC) was externally validated. RESULTS: The training and test sets included 159 and 166 patients, respectively. The median age of patients in the test set was 55 years; 72.3% of them had stage III tumors, and 65.4% underwent complete cytoreduction. Metabolic tumor volume, total lesion glycolysis, and the number of metastatic lesions above the upper margin of the renal vein (area A) were selected among the PET/CT parameters. The best predictive multivariable model consisted of CA-125 (<750 or ≥750 IU/mL), number of metastatic lesions (<2 or ≥2), and metabolic tumor volume of area A, predicting complete cytoreduction with an AUC of 0.768. The model was validated using a test set. Its predictive performance yielded an AUC of 0.771. CONCLUSIONS: We successfully developed and validated a preoperative model to predict complete cytoreduction in advanced OC. This model can facilitate patient selection for primary CRS in clinical practice.

Recognition and attitudes of Korean physicians toward fecal microbiota transplantation: a survey study.

BACKGROUND/AIMS: Fecal microbiota transplantation (FMT) represents a treatment option for recurrent Clostridioides difficile infection (CDI). Recently, FMT has been investigated in various clinical settings other than CDI. This study examined Korean physicians' recognition of FMT and their attitudes toward this procedure. METHODS: An online questionnaire included questions on indications for FMT, the FMT process, physicians' attitudes toward FMT for the treatment of CDI and non-CDI diseases, and possible concerns. RESULTS: Finally, 107 physicians responded to this survey: 66 (61.7%) had experience of performing FMT, and 86 (80.4%) replied that they were willing to perform FMT for CDI. Two-thirds of physicians (63.6%, n = 68) would perform FMT for recurrent CDI on patients who had at least three recurrences. The most common obstacle to performing FMT for the treatment of CDI was the lack of regulations or guidelines (55.1%, n = 59). Seventy-seven (72.0%) physicians would consider FMT for non- CDI diseases when conventional treatment had failed. The most common obstacle for FMT for the treatment of non-CDI diseases was low treatment efficacy (57.0%, n = 61). CONCLUSION: Two-thirds of Korean physicians had experience of performing FMT, and many performed FMT for recurrent CDI. The results of this study will prove useful to researchers and practitioners in FMT in Korea.

Anchoring endoscopic mucosal resection versus conventional endoscopic mucosal resection for large nonpedunculated colorectal polyps: a randomized controlled trial.

BACKGROUND : Colorectal polyps > 10 mm in size are often incompletely resected. Anchoring-endoscopic mucosal resection (A-EMR) is the technique of making a small incision at the oral side of the polyp using a snare tip after submucosal injection to avoid slippage during ensnaring. This study was performed to evaluate whether A-EMR could increase the complete resection rate for large colorectal polyps compared with conventional endoscopic mucosal resection (C-EMR). METHODS : Polyps with sizes of 10-25 mm were randomly allocated to either the A-EMR or the C-EMR groups. RESULTS : 105 and 106 polyps were resected using A-EMR and C-EMR, respectively. In the intention-to-treat population, the complete resection rate was 89.5 % in the A-EMR group and 74.5 % in the C-EMR group (relative risk [RR] 1.20, 95 %CI 1.04 to 1.38; P = 0.01). The en bloc resection rates for the A-EMR and C-EMR groups were 92.4 % vs. 76.4 % (RR 1.21, 95 %CI 1.06 to 1.37; P = 0.005) and R0 resection rates were 77.1 % vs. 64.2 % (RR 1.18, 95 %CI 0.98 to 1.42; P = 0.07), respectively. The median (interquartile range [IQR]) total procedure time was 3.2 (2.6-4.1) minutes in the A-EMR group and 3.0 (2.2-4.6) minutes in the C-EMR group (median difference 0.2 minutes, 95 %CI -0.22 to 0.73; P = 0.25). There was one episode of delayed bleeding and one perforation in the C-EMR group. CONCLUSIONS : A-EMR was superior to C-EMR for the complete resection of large colorectal polyps. A-EMR can be considered one of the standard methods for the removal of colorectal polyps of 10 mm or more in size.

Long-term outcomes after endoscopic versus surgical resection of T1 colorectal carcinoma.

BACKGROUND: The long-term outcomes of patients with T1 colorectal cancer (CRC) who undergo endoscopic and/or surgical treatment are not well understood. Invasive CRC confined to the colonic submucosa (T1 CRC) is challenging in terms of clinical decision-making. We compared the long-term outcomes of T1 CRC by treatment method. METHODS: We examined 370 patients with pathological T1 CRC treated between 2000 and 2015 at Seoul St. Mary's Hospital. In total, 93 patients underwent endoscopic resection (ER) only, 82 underwent additional surgery after ER, and 175 underwent surgical resection only. Patients who did not meet the curative criteria were defined as "high-risk." High-risk patients were classified into three groups according to the treatment modalities: ER only (Group A: 35 patients), additional surgery after ER (Group B: 72 patients), and surgical resection only (Group C: 133 patients). The recurrence-free and overall survival (OS) rates, and factors associated with recurrence and mortality, were analyzed. Factors associated with lymph node metastasis (LNM) were subjected to multivariate analysis. RESULTS: Of the 370 patients, 7 experienced recurrence and 7 died. All recurrences occurred in the high-risk group and two deaths were in the low-risk group. In high-risk groups, there was no significant group difference in recurrence-free survival (P = 0.511) or OS (P =0.657). Poor histology (P =0.042) was associated with recurrence, and vascular invasion (P =0.044) with mortality. LNMs were observed in 30 of 277 patients who underwent surgery either initially or secondarily. Lymphatic invasion was significantly associated with the incidence of LNM (P < 0.001). CONCLUSIONS: ER prior to surgery did not affect the prognosis of high-risk T1 CRC patients, and did not worsen the clinical outcomes of patients who required additional surgery. Lymphatic invasion was the most important predictor of LNM.