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Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases 1 , 2 . However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation 3 . Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo 4 . Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies. A culture system allows the long-term expansion of human haematopoietic stem cells (HSCs) in vivo without the use of recombinant cytokines or albumin, with potential applications for clinical therapies involving HSCs.

Locally advanced and metastatic urothelial carcinoma (UC) remains a challenging malignancy, though several novel therapeutic drugs have been developed in recent years. Over the past decade, immune checkpoint inhibitors (ICI) have shifted the paradigm of therapeutic strategies for UC; however, only a limited number of patients respond to ICI. Since radiotherapy (RT) is widely known to induce systemic immune activation, it may boost the efficacy of ICI. Conversely, RT also causes exhaustion of cytotoxic T cells, and the activation and recruitment of immunosuppressive cells; ICI may help overcome these immunosuppressive effects. Therefore, the combination of ICI and RT has attracted attention in recent years. The therapeutic benefits of this combination therapy and its optimal regimen have not yet been determined through prospective studies. Therefore, this review article aimed to provide an overview of the current preclinical and clinical studies that illustrate the underlying mechanisms and explore the optimization of the RT regimen along with the ICI and RT combination sequence. We also analyzed ongoing prospective studies on ICI and RT combination therapies for metastatic UC. We noted that the tumor response to ICI and RT combination seemingly differs among cancer types. Thus, our findings highlight the need for well-designed prospective trials to determine the optimal combination of ICI and RT for locally advanced and metastatic UC.

Fatty liver is known to be associated with extra-hepatic diseases including atherosclerotic cardiovascular disease and extra-hepatic cancers, which affect the prognosis and quality of life of the patients. The inter-organ crosstalk is mediated by metabolic abnormalities such as insulin resistance and visceral adiposity. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a new definition for fatty liver. MAFLD is characterized by the inclusion criteria of metabolic abnormality. Therefore, MAFLD is expected to identify patients at high risk of extra-hepatic complications. In this review, we focus on the relationships between MAFLD and multi-organ diseases. We also describe the pathogenic mechanisms of the inter-organ crosstalk.

Background Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection may result in complications or may be unsuitable for tumors that are difficult to treat endoscopically. We investigated the usefulness of a newly developed endoscopic resection technique—EMR with an over‐the‐scope clip (EMR‐O)—for difficult‐to‐treat lesions. Method We retrospectively examined patients who underwent EMR‐O for colorectal tumors between September 2017 and January 2024. Patient and lesion characteristics, technical success rates, en bloc resection rates, R0 resection rates, procedure time, histopathology, and the clinical course were evaluated. Results EMR‐O was performed for 18 patients. Indications for EMR‐O included residual or recurrent lesions (seven patients; 38.9%), diverticulum lesions (five patients; 27.8%), appendiceal orifice lesions (three patients; 16.7%), T1 cancers (two patients; 11.1%), and subepithelial tumors (one patient; 5.5%). The median lesion size was 11 mm. The rates of technical success, en bloc resection, and R0 resection were 100%, 86.7%, and 86.7%. The median procedure time was 10 min. The only adverse event was diverticulitis (one patient; 5.5%). Intraoperative and delayed perforation and bleeding were not observed. The pathological resection depths were full‐thickness for three patients (16.7%), muscularis resection for four patients (22.2%), and deep submucosal resection for 11 patients (61.1%). Conclusion Although EMR‐O is limited by the target lesion size, it shortens the procedure time, prevents perforation, and avoids the need for surgery. EMR‐O may be a minimally invasive treatment option for small lesions that are difficult to treat endoscopically.

Aim To develop a trauma surgery training program using porcine organs and evaluate its usefulness. This program allows participants to experience the tactile sensation of organs and bleeding, which are impossible in trauma surgery training using a cadaver. Methods Resected organs (heart, lung, liver, spleen, kidney, small intestine, bladder, and external carotid artery) from slaughtered pigs for medical research were perfused with saline solution, flash‐frozen in a deep freezer, and thawed naturally on the morning of training. The training program consisted of half‐day practical training in suture repair of artificially created damage to the parenchymal organs and suture or anastomotic repair of damage to the luminal organs. We injected the parenchymal organs' arteries with porcine blood and the renal ureters with saline solution to create models of organ hemorrhage and urinary leakage. The training's usefulness was evaluated using a participant questionnaire that included an 11‐point self‐assessment of confidence level (SACL) form. Results Nine training seminars were conducted from September 2018 to February 2023, attended by 67 participants who were in their 1st to 20th post‐graduate year. The mean SACL significantly increased immediately after the seminar but decreased half‐year thereafter. However, it was maintained for those with surgical residency. It was also maintained for those with no surgical residency through seminar repetition. Conclusions Training in trauma surgical techniques using porcine organs is beneficial regardless of whether the participant has prior surgical residency. Training in trauma surgical techniques using porcine organs is beneficial regardless of whether the participant has prior surgical residency.

Lenvatinib is available as a molecular target agent for hepatocellular carcinoma (HCC). In this study, we investigated the popping phenomena in patients with HCC who underwent radiofrequency ablation (RFA) after taking lenvatinib. Fifty-nine patients with HCC between 21-30 mm in diameter and no history of systemic treatment were enrolled in the study. The patients underwent RFA using a VIVA RFA SYSTEM with an ablation tip of 30 mm in length. For the initial lenvatinib administration, 16 patients had an adequate course of treatment and were treated with RFA as add-on therapy (combination group). The other 43 patients were treated by RFA monotherapy (monotherapy group). The popping frequency during RFA was recorded and compared. Popping frequency in the combination group (RFA combined with lenvatinib) was significantly higher than that in the monotherapy group. There was no significant difference between the combination group and the monotherapy group in ablation time, maximum output level, tumour temperature after ablation, or initial resistance value. Popping frequency was significantly higher in the combination group. It is possible that the intra-tumour temperature increased rapidly during RFA in the combination group due to the inhibitory effect of lenvatinib on tumour angiogenesis, leading to the occurrence of popping. Further studies are needed to investigate popping after RFA, and precise protocols need to be developed.

Abstract Introduction: Patients with Crohn’s disease (CD) require an assessment of small bowel lesions, while difficulties exist in performing small intestinal examinations, especially in small-sized medical offices. Small bowel capsule endoscopy (SBCE) is handy and can be performed in most clinical settings. The only drawback of SBCE is a requirement of patency testing prior to the exam because it sometimes requires CT scanning to localize the ingested patency capsule (PC), which may be a substantial burden for the patient. We have developed a novel PC detection system named PICS (patency capsule, ileocolonoscopy, and small bowel capsule endoscopy) method by which we can avoid CT scanning. In the PICS method, ileocolonoscopy (ICS) is performed after 30–33 h of PC ingestion and the PC can be localized by ICS in patients who have not excreted the PC, and the entire intestine can be examined in combination with subsequent SBCE without additional bowel preparation. The aim of this study was to assess the usefulness and safety of the PICS method for CD patients. Methods: CD patients who underwent PICS method from April 2021 to March 2023 were reviewed for clinical data, outcome of PICS method including the rates of PC detection by ICS, the number of patients underwent SBCE, and adverse events. Lewis score was used to assess SBCE results. Results: The PICS method was performed in 54 patients. The median age of patients was 28.5 years old, and 64.8% of them were ileocolic type. The median disease duration was 10.5 months and 24.1% had history of small bowel resection. Five cases (9.3%) confirmed gastrointestinal patency by ICS, and none of the cases required CT scanning. One patient who could not be confirmed patency by ICS, and the other patient who excreted PC but was found ileal stenosis by ICS did not undergo SBCE. Remaining 52 patients received SBCE, and the median Lewis score of them was 0 (IQR 0, 450). There were no adverse events including small bowel obstruction by PC and SBCE retention in this series. Conclusion: The PICS method is not only feasible and safe but also convenient to assess disease extent in patients with CD. By localizing PC with ICS, additional CT scanning could be unnecessary for SBCE, which benefits both physicians and CD patients.

Ablating a spherical area during hepatocellular carcinoma ablation therapy is a very important issue. We aimed to determine the ablation area of bovine liver using various radiofrequency ablation (RFA) protocols. Bovine liver (1-2 kg) was placed in an aluminum tray, which was punctured with STARmed VIVA 2.0 17-gauge (G) and 15-G electrodes using a current-carrying tip. Under the step-up or linear method, with an ablation time up to one break and RFA output stop, the size of the color change area (representing the thermally coagulated area) of the bovine liver was measured along the vertical and horizontal axes, and the ablated volume and total heat generated were calculated. 5-W per minute increases protocol resulted in greater horizontal and vertical diameters of the ablated area than 10-W per minute increases protocol under the step-up method. For 5-W and 10-W per minute increases under the step-up method, the aspect ratio was 0.81 and 0.67 with a 17-G electrode, and 0.73 and 0.69 with a 15-G electrode, respectively. For 5-W and 10-W increases under the linear method, the aspect ratio was 0.89 and 0.82, respectively. Sufficient ablation was obtained, with vertical and horizontal diameters of 50 mm and 43.50 mm, respectively. Although the ablation time was long, the watt output value at the break and average watt value were low. Gradual increase in output (5 W) using the step-up method yielded a more spherical ablation area, and longer ablation time in the linear method with a 15-G electrode could result in a more spherical ablation area in real clinical practice in humans. Future studies should examine concerns regarding long ablation times.

ABSTRACT The lytic bacteriophage pT24, which infects Tenacibaculum spp., was isolated from the water of a whiteleg shrimp (Litopenaeus vannamei) culture pond in Thailand. This giant bacteriophage with myovirus morphology comprised 234,670 bp with 296 predicted genes.