Recent Developments of Nontraditional Single-Molecule Toroics.

Single-molecule toroics (SMTs), defined as a type of molecules with toroidal arrangement of magnetic moment associated with bi-stable non-magnetic ground states, are promising candidates for high-density information storage and the development of molecule based multiferroic materials with linear magneto-electric coupling and multiferroic behavior. The design and synthesis of SMTs by arranging the magnetic anisotropy axis in a circular pattern at the molecular level have been of great interest to scientists for last two decades since the first detection of the SMT behavior in the seminal Dy3 molecules. DyIII ion has long been the ideal candidate for constructing SMTs due to its Kramer ion nature as well as high anisotropy. Nevertheless, other LnIII ions such as TbIII and HoIII ions, as well as some paramagnetic transition metal ions, have also been used to construct many nontraditional SMTs. Therefore, we review the progress in the studies of SMTs based on the nontraditional perspective, ranging from the 3D topological to 1D&2D&3D polymeric SMTs, and 3d-4f to non Dy-based SMTs. We hope the understanding we provide about nontraditional SMTs will be helpful in designing novel SMTs.

Risk factors for complications and incomplete resection after endoscopic resection for duodenal submucosal tumors.

BACKGROUND AND AIM: Endoscopic resection (ER) has been used to remove submucosal tumors (SMTs) in recent years; however, duodenal ER is associated with high rates of immediate or delayed bleeding and perforation. Whether ER can be recommended for the treatment of duodenal SMTs remains controversial. Therefore, we aimed to investigate the clinical outcomes associated with the ER of duodenal SMTs and to assess possible predictive factors for complications and incomplete resection. METHODS: This retrospective study included 141 patients with duodenal SMTs. The therapeutic outcomes from ER and procedure-related complications were analyzed. RESULTS: Of the 141 patients, 78.7% achieved complete resection and nine (6.4%) developed complications. The multivariate analysis suggested that location near the duodenal papilla (P = 0.010) and diameter exceeding 15 mm (P = 0.091) of duodenal SMTs were independent risk factors for complications in ER. Besides, submucosal fibrosis (P = 0.042), location near the duodenal papilla (P = 0.049), and irregular morphology (P = 0.067) were independent risk factors for incomplete resection. CONCLUSIONS: ER can be recommended as an effective and minimally invasive treatment for duodenal SMTs.

Gastric defect closure after endoscopic full-thickness resection: the closing while dissecting technique.

BACKGROUND: Complete closure of gastric wall defects is critical following endoscopic full-thickness resection (EFTR). The aim of this study was to evaluate the efficacy, safety, and clinical outcome of a new endoscopic method: closing while dissecting. METHODS: Twenty-seven patients who underwent EFTR were retrospectively analyzed between January 2020 and March 2021. Gastric defects resulting from EFTR were closed using the "interrupted-close during dissection" technique with endoclips. Tumor characteristics, en bloc resection rates, and postoperative adverse events were evaluated. RESULTS: All submucosal tumors were successfully resected and complete resection was histologically confirmed. The mean maximal tumor diameter was 1.3 cm (ranging from 0.8 to 3.0 cm). The majority of these tumors were gastrointestinal stromal tumors (n = 20), Leiomyoma (n = 3), schwannomas (n = 2), others included fibroma (n = 1) and neurogenic tumor (n = 1). There were no cases of hemorrhage, peritonitis, or delayed perforation. Four patients complained of slight abdominal pain, but no hyperpyrexia or serious elevated white blood cell count was detected in the first 24 h after treatment. All wounds were healed on follow-up endoscopy 3 months after the procedure. The mean follow-up duration was 8.5 months (ranging from 3 to 17) and no tumor recurrences were observed. CONCLUSIONS: The feasibility and safety of this interrupted-close during dissection approach allows for clinical applications in EFTR of gastric submucosal tumors.

The retrospective comparison between submucosal tunneling endoscopic resection and endoscopic submucosal excavation for managing esophageal submucosal tumors originating from the muscularis propria layer.

BACKGROUND: Submucosal tunneling endoscopic resection (STER) and endoscopic submucosal excavation (ESE) were recently introduced to cure submucosal tumors (SMTs) originating from the muscularis propria (MP) layer. This study aimed to compare clinical performance and safety of STER and ESE in treating esophageal SMTs originating from the MP layer. METHODS: From January 2011 to December 2017, retrospective data collection and follow-up were applied for all STER or ESE cases with esophageal SMTs originating from the MP layer in our endoscopy center, including clinical characteristics, procedure success, efficacy, and adverse events. Subgroup analysis was further done based on tumor size and origin. RESULTS: 90 STER and 77 ESE were enrolled in this study. There were no significant difference for patient characteristics, procedure performance, and complications for ESE and STER intervention (P > 0.05). STER was faster than ESE (3.90 mm2/min vs 2.82 mm2/min, P < 0.05). For large tumors (≥ 20 mm), both techniques had the similar performance (P > 0.05), while STER led to the shorter hospitalization (4.0d vs 7.0d, P < 0.05) and lower postoperative complication (16.3% vs 45.5%, P < 0.05). For small tumors (< 20 mm), STER achieved faster operation (STER vs ESE, 2.57 mm2/min vs 1.83 mm2/min, P < 0.05). Regardless of tumor origin, there were no significant difference for both techniques, but STER resulted in short hospitalization for SMTs from the deep MP layer (STER vs ESE, 5.0d vs 7.0d, P < 0.05). During the follow-up, 2 residual and 4 recurrence occurred in the STER group, as well as 1 residual and 2 recurrence in the ESE group. CONCLUSIONS: Both STER and ESE were effective for treating esophageal SMTs originating from the MP layer. STER might be better due to its faster operation, less complications, and shorter hospitalization.

Multiband mucosectomy versus endoscopic submucosal dissection and endoscopic submucosal excavation for GI submucosal tumors: short and long term follow-up.

AIMS: To evaluate the short- and long-term outcomes of 3 different endoscopic dissection techniques for upper gastrointestinal (GI) submucosal tumours (SMTs). METHODS: Data for 135 patients withGI SMTs who underwent multiband mucosectomy (MBM), endoscopic submucosal dissection (ESD), or endoscopic submucosal excavation (ESE) were retrospectively assessed. The en bloc resection rate, endoscopic complete resection rate, operation time, potential complications and local recurrence rate were compared. RESULTS: No significant differences were observed in the rate of endoscopic complete resections and pathologic complete resections among the three groups. For SMTs > 15 mm in width, the lowest en bloc resection rate was found for MBM (P = 0.000). MBM was also associated with the shortest procedure time, lowest perforation rate and lowest rate of major bleeding. ESE was the most effective procedure for muscularis propria (MP) lesions but was associated with the longest operation time (P < 0.01). The ESD and ESE groups had similar perforation rates (P > 0.05). No differences were observed in 4-year local recurrence rates among the groups (P = 0.945). CONCLUSIONS: MBM is a simple and effective method for the treatment of small SMTs and achieves clinical success rates similar to those of ESD and ESE. However, ESD and ESE are preferable for larger and deep lesions and are associated with a longer operation time. Nonetheless, all 3 techniques resulted in a low 4-year local recurrence rate. Large-scale randomized clinical trials are needed to further investigate these results.

Coated microneedles for transdermal delivery of a potent pharmaceutical peptide.

Minimally invasive delivery of peptide and protein molecules represents a significant opportunity for product differentiation and value creation versus standard injectable routes of administration. One such technology utilizes microneedle (MN) patches and it has made considerable clinical advances in systemic delivery of potent macromolecules and vaccines. A sub-class of this technology has focused on preparation of solid dense MN arrays followed by precision formulation coating on the tips of the MN. The objective of this study was to develop a drug product using the MN technology that has similar bioperformance when compared to subcutaneous route of delivery and can provide improved stability under storage. Therapeutic peptide (Peptide A, Merck & Co., Inc., Kenilworth, NJ, USA) is being developed as a subcutaneous injection for chronic dosing with a submilligram estimated therapeutic dose. Peptide A has chemical and physical stability challenges in solution and this led to exploration of a viable drug product which could provide therapeutic dosages while overcoming the stability issues seen with the compound. This work focused on developing a coated solid microstructure transdermal system (sMTS) for Peptide A followed by detailed in vitro and preclinical evaluation for two different coating formulations. Based on initial assessment, ~250 µg of Peptide A could be coated with precision on a 1.27cm2 patch which contained 316 MN's. The delivery from these systems was achieved with absolute bioavailability being similar to the subcutaneous delivery (88% and 74% for coated sMTS 1 & 2 and 75% for subcutaneous delivery). Stability of Peptide A was also found to be significantly improved when coated on the sMTS system with minimal degradation recorded at room temperature storage as compared to the subcutaneous liquid formulation. Additionally, skin irritation (on pig skin) was also measured in this study and it was found to be minimal and self-resolving. This evaluation provided a viable option for developing a drug product with improved stability and successful delivery of the investigated molecule. Graphical abstractSchematic showing uncoated sMTS, resulting product with coated peptide, successful skin penetration with high delivery efficiency and bioavailability.

Precutting endoscopic band ligation-assisted resection versus endoscopic submucosal dissection in patients with small gastric submucosal tumors originating from the muscularis propria: study protocol of a randomized controlled trial.

BACKGROUND: The management of small gastric submucosal tumors (SMTs) originating from the muscularis propria layer (SMT-MPs) remains a subject of debate. Endoscopic submucosal dissection (ESD) is currently considered the optimal treatment for resection. However, high expenses, complex procedures, and the risk of complications have limited its application. Our previously proposed novel operation, precutting endoscopic band ligation (precutting EBL), has been demonstrated in a long-term, single-arm study to be an effective and safe technique for removing small gastric SMTs. However, the absence of a pathological examination and the potential for delayed perforation have raised concerns. Thus, we modified the precutting EBL by adding endoscopic resection to the snare after ligation and closure, yielding the precutting endoscopic band ligation-assisted resection (precutting EBLR). Moreover, the initial pilot study confirmed the safety and efficacy of the proposed approach and we planned a randomized controlled trial (RCT) to further validate its clinical feasibility. METHODS: This was a prospective, single-center, open-label, parallel group, and randomized controlled trial. Approximately 40 patients with SMT-MPs will be included in this trial. The patients included were allocated to two groups: ESD and precutting EBLR. The basic clinical data of the patients were collected in detail. To better quantify the difference between ESD and precutting EBLR, the primary outcome was set as the operation duration. The secondary outcomes included total operation cost and hospitalization, intraoperative adverse events, and postoperative recurrence. The primary outcome was tested for superiority, while the secondary outcomes were tested for noninferiority. SPSS is commonly used for statistical analysis. DISCUSSION: This study was designed to validate the feasibility of a novel operation for removing gastric SMT-MPs. To intuitively assess this phenomenon, the operation durations of precutting EBLR and ESD were compared, and other outcomes were also recorded comprehensively. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200065473 . Registered on November 5, 2022.

Efficacy and Safety of Transdermal Abaloparatide in Postmenopausal Women with Osteoporosis: A Randomized Study.

Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide-sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (N = 511) 1:1 to open-label abaloparatide administered daily via abaloparatide-sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE: 0.46%) for abaloparatide-sMTS and 10.86% (SE: 0.48%) for abaloparatide-SC (treatment difference: -3.72% [95% confidence interval: -5.01%, -2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide-sMTS and 3.70% for abaloparatide-SC. Median changes from baseline at 12 months in serum procollagen type I N-terminal propeptide (s-PINP) were 52.6% for abaloparatide-sMTS and 74.5% for abaloparatide-SC. Administration site reactions were the most frequently reported adverse events (abaloparatide-sMTS, 94.4%; abaloparatide-SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide-sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide-sMTS to abaloparatide-SC for percentage change in spine BMD at 12 months was not demonstrated; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Submucosal Tunneling Techniques for Tumor Resection.

The concept of third space endoscopy is based on the principle that the deeper layers of the gastrointestinal tract can be accessed by tunneling in the submucosal space and maintaining the integrity of the overlying mucosa. The mucosal flap safety valve enabled endoscopists to use submucosal space securely. The era of third space endoscopy started with peroral endoscopic myotomy for treatment of achalasia and has expanded to treat various other gastrointestinal disorders, such as mucosal lesions, submucosal tumors, extraluminal tumors, and refractory gastroparesis, Zenker diverticulum, and restoration of the completely obstructed esophageal lumen. Third space endoscopy rapidly emerged as a minimally invasive alternative to conventional surgery. Many studies discovered that this technique is safe and effective with excellent outcomes. Our review focused on the indications, techniques, clinical management, and adverse events of submucosal tunneling techniques for tumor resection.

Robotic-assisted surgery for esophageal submucosal tumors: a single-center case series.

Esophageal submucosal tumors (SMTs) are rare heterogenous clinical entities. The surgical resection can be performed in different surgical approaches. However, the robotic surgical strategy is poorly documented in the treatment of SMTs. We present our series of operated esophageal SMTs approached via robotic-assisted surgery. Six patients with symptomatic esophageal submucosal tumors underwent robotic surgery within a 3-year period. The performed procedures were robotic-assisted enucleation, robotic esophagectomy (RAMIE) and reverse hybrid robotic esophagectomy. Patients' clinical data, intra/postoperative outcomes, and histopathological features were retrieved from the institution's prospective database. Five of six patients were scheduled for upfront surgery: four underwent robotic enucleation (three leiomyoma and one suspected GIST) and one underwent reverse hybrid robotic esophagectomy (suspected GIST). One patient, diagnosed with GIST, was treated with neoadjuvant Imatinib therapy, before undergoing a RAMIE. No major intra-operative complications were recorded. Median length of stay was 7 days (6-50), with a longer post-operative course in patients who underwent esophagectomy. Clavien-Dindo > 3a complications occurred in two patients, aspiration pneumonia and delayed gastric emptying. The final histopathological and immuno-histochemical diagnosis were leiomyoma, well-differentiated GIST, low-grade fibromyxoid sarcoma and Schwannoma. Robotic-assisted surgery seems to be a promising option for surgical treatment strategies of benign or borderline esophageal submucosal tumors.

The influence of training procedure and stimulus valence on the long-term maintenance of equivalence relations.

In the current research, we aimed at extending Silveira et al. (2016) results by verifying whether the long-term maintenance of the equivalence classes is influenced by stimulus valence and MTS training procedures. The delayed and simultaneous MTS were used to train two groups of participants in series of conditional relation trials involving pictures of humans' faces expressing familiar emotions (A) and abstract forms (B, C, and D). The participants that demonstrated the emergence of novel BD and DB relations and class-consistent derived transfer of functions returned to the laboratory thirty days later. Follow-up assessments were given in which the probability of class-consistent responses was higher for the happy class only for participants exposed to DMTS training. This result shows that the maintenance of equivalence classes cannot be accounted for only in terms of the affective valence of the familiar stimulus. The affective valence of the happy faces may have yoked with the properties of DMTS, favoring the maintenance of the happy class. Thereby, we discussed the role of mediating verbal behavior evoked selectively by the pictures of happy faces appearing as samples that may have persisted during the delay interval as a possible mechanism underlying performances of participants trained in DMTS procedure.

Combination of laparoscopic and endoscopic approaches for neoplasia with non-exposure technique (CLEAN-NET) for gastric submucosal tumors: updated advantages and limitations.

Laparoscopic and endoscopic cooperative surgery (LECS) for gastric submucosal tumors (SMTs) has been developed under the concept of resecting gastric tumors with both complete curability and preserving organ functions. Precise resection is obtained by classical LECS, however, concerns regarding intraoperative bacterial infection and dissemination of the tumor cells into the abdominal cavity by LECS with exposure technique still remain. To prevent these concerns, several LECS-related procedures with non-exposure techniques, such as combination of laparoscopic and endoscopic approaches for neoplasia with non-exposure technique (CLEAN-NET) and non-exposed endoscopic wall-inversion surgery (NEWS), have been reported to be safe and feasible. Classical LECS, CLEAN-NET, and NEWS have the same concept, however, each has its own different characteristic procedures; exposure or non-exposure technique, inversion of the tumor into or outer the lumen, retrieval of tumor per oral or through the abdominal cavity, and dominance in the role of the endoscopist or the laparoscopic surgeon. Familiarization with these procedure details is important to understand their indications, advantages and limitations, resulting in providing a tailored minimally invasive surgery for patients. The main scope of this review article is to introduce readers to the clinical application, procedure, and results of CLEAN-NET, both from previous literatures and from our experience, as well as to offer a closer look at its advantages and limitations while comparing with other LECS procedures from the viewpoint of introducing CLEAN-NET first.

Laparoscopic and endoscopic cooperative surgery for gastrointestinal tumor.

With technological progress of endoscopic submucosal dissection (ESD) in the last decade, several laparoscopic and endoscopic cooperative surgeries (LECS) for gastrointestinal tumor have recently been developed. LECS is definitely favorable to the minimization of surgical margin, which leads to functional and anatomical preservation of gastrointestinal tract. LECS for gastrointestinal tumor is mainly sorted by two categories: exposure procedures and non-exposure procedures between endoluminal and extraluminal spaces. Exposure procedures have the potential risk of gastric contents or tumor cells spilling out over the abdominal cavity, because the stomach wall has to be perforated intentionally during the procedure. In order to avoid the potential these risks, non-exposure procedures have been developed. Currently, the LECS concept has rapidly permeated for treatment of gastrointestinal tumor due to its certainty and safety, although there is still room for improvement to lessen its technical difficulty. This review describes the current LECS for gastrointestinal tumor based on the several articles.

Endoscopic ultrasound-guided fine-needle aspiration skill acquisition of gastrointestinal submucosal tumor by trainee endoscopists: A pilot study.

BACKGROUND AND OBJECTIVES: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is an effective method for tissue diagnosis of gastrointestinal submucosal tumors (SMTs) that are difficult to diagnose by standard endoscopic biopsy. However, the learning curve, especially for gastrointestinal SMT, has not been sufficiently established. The aim of our study was to assess the skill acquisition and diagnostic accuracy of EUS-FNA for gastrointestinal SMT in trainee endoscopists in order to elucidate the optimal starting standards of EUS-FNA. MATERIALS AND METHODS: We prospectively evaluated 51 EUS-FNA procedures for gastrointestinal SMT between May 2010 and March 2014. The procedure was performed by two trainee endoscopists and two expert endoscopists. We investigated the diagnostic yield of EUS-FNA and the factors associated with the accuracy between the trainee endoscopists and expert endoscopists. RESULTS: The rate of adequate EUS-FNA materials for histological examination was 86.3%. Although infections occurred in two cases (3.9%), which were managed conservatively, no severe complications were identified. Comparing the trainee endoscopists with expert endoscopists, there was no significant difference in the rate of gaining adequate specimen (76.5% vs. 82.3%, P = 0.4626). However, the mean number of passes of the trainees tended to be more than that of the expert endoscopists (2.1 pass vs. 1.7 pass, P = 0.0511), and lesions located in the middle third of the stomach were the predictive factors for nondiagnostic tumors by the trainee endoscopists (P = 0.0075). CONCLUSION: EUS-FNA for gastrointestinal SMT by trainee endoscopists can be safely performed under the supervision of EUS-FNA expert endoscopists.