Nanocarriers' repartitioning of drugs between blood subcompartments as a mechanism of improving pharmacokinetics, safety, and efficacy.

For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers. We focus on fingolimod, a small molecule drug that is FDA-approved for treatment of multiple sclerosis, which has also shown promise in the treatment of stroke. Unfortunately, fingolimod has poor solubility and very extensive partitioning to plasma proteins and RBCs (in whole blood, 86% partitions to RBCs, 13.96% to plasma proteins, and 0.04% is free). We develop a liposomal formulation that slows the partitioning of fingolimod to RBCs and plasma proteins, enables intravenous delivery, and additionally prevents fingolimod toxicity to RBCs. The liposomal formulation nearly completely prevented fingolimod adsorption to plasma proteins (association with plasma proteins was 98.4 ±â€¯0.4% for the free drug vs. 5.6 ±â€¯0.4% for liposome-loaded drug). When incubated with whole blood in vitro, the liposomal formulation greatly slowed partitioning of fingolimod to RBCs and also eliminated deleterious effects of fingolimod on RBC rigidity, morphology, and hemolysis. In vivo, the liposomal formulation delayed fingolimod partitioning to RBCs for over 30 min, a critical time window for stroke. Fingolimod-loaded liposomes showed improved efficacy in a mouse model of post-stroke neuroinflammation, completely sealing the leaky blood-brain barrier (114 ±â€¯11.5% reduction in albumin leak into the brain for targeted liposomes vs. 38 ±â€¯16.5% reduction for free drug). This effect was only seen for liposomes modified with antibodies to enable targeted delivery to the site of action, and not in unmodified, long-circulating liposomes. Thus, loading fingolimod into liposomes prevented partitioning to RBCs and associated toxicities and enabled targeted delivery. This paradigm can be used for tuning the blood distribution of small molecule drugs for the treatment of acute illnesses requiring rapid pharmacologic intervention.

New surgery technique combining robotics and laparoscopy using the Hugo™ RAS system.

INTRODUCTION: Hybrid total laparoscopic hysterectomy combines conventional laparoscopic surgery and robot-assisted devices: the camera and assistant forceps are operated by a robotic device, whereas the surgeon performs laparoscopic procedures, enabling surgery with a completely fixed field of view and significantly reducing errors in forceps grasping and needle misalignment. Here, we examined whether using two arms of the Hugo™ robot-assisted surgery system, one for the camera and one for the assistant, would improve surgical accuracy compared with conventional total laparoscopic hysterectomy. MATERIALS AND SURGICAL TECHNIQUE: The surgical system reduced surgeon errors in grasping the forceps during training and stabilized forceps operation. Compared with conventional laparoscopic surgery, the use of the surgical system did not result in different operative durations. The stable surgical procedure was considered a major advantage. DISCUSSION: This new technique involving new equipment can improve surgeon training and performance. In the future, we will develop new techniques to improve surgical performance.

[Pulmonary Amyloidosis Observed by Thoracoscopy:Report of a Case].

The case is an 80-year-old woman with Sjögren's syndrome. During the follow-up of multiple pulmonary nodules, an enlarged nodule was observed in the peripheral of the right S3 interlobar region. Fluorodeoxyglucose- positron emission tomography (FDG-PET) showed FDG accumulation only in the S3 nodule, which led to suspicion of primary lung cancer. Because of its difficult location to reach by bronchoscopy, a right lung S3 segmentectomy was performed. Intraoperative findings revealed a hard yellowish- white nodule just below the pleura. Pathological examination showed that the nodule consisted of an acidophilic structureless material, which was positive for Congo red staining and disappeared after permanganate treatment. Based on the above findings, we diagnosed amyloid A( AA)-type amyloidosis. In this case, the nodule was located just below the pleura and we could observe it by thoracoscopy. There have been few reports of thoracoscopic observation of pulmonary amyloidosis, and we report with intraoperative findings.

Comparison of surgical outcomes of da Vinci surgical systems X and Xi: A single-center study.

BACKGROUND: The da Vinci surgical systems (X and Xi) are fourth-generation systems marketed by Intuitive Inc. The X system is less expensive than the Xi system. This study compared the surgical outcomes of patients who underwent hysterectomy using the X and Xi systems. METHODS: Data from 172 patients who underwent robot-assisted total hysterectomies by four surgeons between April 2019 and March 2023 were retrospectively analyzed in a single-center study. The patients were divided into two groups based on the surgical system used. Approval was granted by the Institutional Review Board of the Tottori University Hospital (22A134). All patients provided opt-out consent in accordance with the institutional guidelines. RESULTS: Operative time (126.6 ± 29.5 for X, 138.2 ± 38.5 for Xi, p = .227) and console time (92.9 ± 27.0 for X, 105.5 ± 34.7 for Xi, p = .089) were insignificantly shorter in group X than in group Xi after propensity score matching for age, body mass index, nulliparity, previous history of abdominal or pelvic surgery, preoperative diagnosis, and surgical approach. No significant differences between X and Xi were observed in a subgroup analysis of patients who underwent robot-assisted total laparoscopic hysterectomy without lymphadenectomy (operative time: 199.0 ± 26.5 for X, 221.5 ± 45.1 for Xi, p = .227; console time: 162.1 ± 25.0 for X, 178.3 ± 0.314 for Xi, p = .314). CONCLUSION: Perioperative outcomes for the X and Xi da Vinci surgical systems were equivalent. The cost-effective X system may allow the widespread use of robotic surgeries.

AMIGO2 is involved in the spread of peritoneal metastasis in serous ovarian cancer via promoting adhesion to the peritoneal mesothelial cells.

BACKGROUND: Amphoterin-induced gene and open reading frame 2 (AMIGO2) have been reported to be related to the prognosis of colorectal, gastric, and cervical cancer. However, their association with ovarian cancer remains unclear. This study aimed to elucidate the role of AMIGO2 in ovarian cancer. METHODS: AMIGO2 expression was evaluated using immunohistochemistry in patients with ovarian serous carcinoma. We validated in vitro studies using four serous ovarian cancer cell lines and in vivo studies using a murine model. RESULTS: The AMIGO2-high group had significantly shorter progression-free survival (PFS) than the AMIGO2-low group. The predictive index of the AMIGO2-high group was considerably higher than that of the AMIGO2-low group. The rate of complete cytoreductive surgery was lower in the AMIGO2-high group than in the AMIGO2-low group. Moreover, in vitro studies revealed that four serous ovarian cancer cell lines exhibited AMIGO2 expression and adhesion to mesothelial cells. Adhesion to mesothelial cells was attenuated by AMIGO2 knockdown in SKOV3 and SHIN3 cells. Furthermore, AMIGO2 downregulation in SKOV3 cells significantly suppressed peritoneal dissemination in the murine model. CONCLUSION: These results suggest that high AMIGO2 expression in serous ovarian carcinoma cells contributes to a poor prognosis by promoting peritoneal metastasis through enhanced cell adhesion to mesothelial cells.

Impact of clinical clerkship integrated with clinical ladder on attending physicians' teaching self-efficacy.

BACKGROUND: Self-efficacy plays an important role in enhancing the teaching capabilities of attending physicians (APs). The clinical ladder (CL) is an educational approach developed in the field of nursing education that increases difficulty in an incremental manner. However, no previous study has confirmed the effectiveness of CL in medical education. Therefore, this study aimed to examine the effect of clinical clerkship integrated with clinical ladder (CC-CL) on the self-efficacy of APs. METHODS: Sixth-year medical students participated in CC-CL for 6 months starting from April 2023, and the changes in the self-efficacy of APs were retrospectively evaluated. The students were trained by the APs concurrently, and the achievement levels of each student were shared. The primary outcome measure was the physician teaching self-efficacy questionnaire (PTSQ) score. The PTSQ scores before and after CC-CL were analyzed using the Wilcoxon matched-pair signed-rank test. RESULTS: Fifteen APs from the Department of Pediatric and Child Neurology were included in this study. No significant difference was observed in the total PTSQ scores of the APs before and after CC-CL. However, a significant increase was observed in the PTSQ score of APs who participated for at least 2 h per week over a period of more than 3 months (n = 8) after CC-CL (p = 0.022). Furthermore, APs who had received their pediatrician certification < 10 years ago (n = 8) showed a significant increase in the total PTSQ score after CC-CL (p = 0.022). CONCLUSIONS: CC-CL may play an important role in cultivating the self-efficacy of less experienced APs. Further comparative studies must be conducted in the future to validate the findings of this study.

Characterization of immortalized ovarian epithelial cells with BRCA1/2 mutation.

We aimed to elucidate the mechanism underlying carcinogenesis by comparing normal and BRCA1/2-mutated ovarian epithelial cells established via Sendai virus-based immortalization. Ovarian epithelial cells (normal epithelium: Ovn; with germline BRCA1 mutation: OvBRCA1; with germline BRCA2 mutation: OvBRCA2) were infected with Sendai virus vectors carrying three immortalization genes (Bmi-1, hTERT, and SV40T). The immunoreactivity to anti-epithelial cellular adhesion molecule (EpCAM) antibodies in each cell line and cells after 25 passages was confirmed using flow cytometry. Chromosomes were identified and karyotyped to detect numerical and structural abnormalities. Total RNA extracted from the cells was subjected to human transcriptome sequencing. Highly expressed genes in each cell line were confirmed using real-time polymerase chain reaction. Immortalization techniques allowed 25 or more passages of Ovn, OvBRCA1, and OvBRCA2 cells. No anti-EpCAM antibody reactions were observed in primary cultures or after long-term passages of each cell line. Structural abnormalities in the chromosomes were observed in each cell line; however, the abnormal chromosomes were successfully separated from the normal structures via cloning. Only normal cells from each cell line were cloned. MMP1, CCL2, and PAPPA were more predominantly expressed in OvBRCA1 and OvBRCA2 cells than in Ovn cells. Immortalized ovarian cells derived from patients with germline BRCA1 or BRCA2 mutations showed substantially higher MMP1 expression than normal ovarian cells. However, the findings need to be validated in the future.

Outcome of robot-assisted surgery for stage IA endometrial cancer compared to open and laparoscopic surgeries: a retrospective study at a single institution.

Few studies have compared the efficacy of robot-assisted, laparoscopic, and open surgeries for endometrial cancer. When considering the position of robotic surgery in Japan, it was necessary to determine whether it was effective or not. We aimed to compare the efficacy and safety of these three types of surgeries for early-stage endometrial cancer. In total, 175 patients with endometrial cancer of preoperative stage IA, who had undergone laparotomic (n = 80), laparoscopic (n = 40), or robot-assisted (n = 55) modified radical hysterectomy at our hospital from 2010 to 2022, were included; surgical outcomes, perioperative complications, and prognoses were compared. Total operative and console times for robot-assisted surgery between patients who did or did not undergo pelvic lymphadenectomy were assessed. The robot-assisted group had the shortest total operative time. The estimated blood loss was lower in the laparoscopic and robot-assisted groups than in the laparotomy group. In advanced postoperative stage IA cases, there were no differences in progression-free and overall survival among the three groups. In the robot-assisted group, the operative time decreased as the number of operations increased; the learning curve was reached after 10 cases each of patients with and without pelvic lymphadenectomy. The frequency of perioperative complications of Clavien-Dindo classification Grade 1 or higher was the lowest in the robot-assisted group (p = 0.02). There were no complications of Clavien-Dindo classification Grade 2 or higher in the robot-assisted group. Robot-assisted surgery for stage IA endometrial cancer, a minimally invasive procedure, has fewer operative times and complications than those of laparoscopic and open surgeries in a single institution in Japan.

Combined resection of lung cancer and thoracic aortic wall with simultaneous thoracic aortic endografting: a case report.

BACKGROUND: Combined resection of lung cancer and the thoracic aortic wall with thoracic aortic endografting has been reported. However, whether the resection and endografting should be performed simultaneously or in two steps remains controversial. CASE PRESENTATION: A 68-year-old man was referred to our hospital because of left chest pain. Chest contrast-enhanced computed tomography revealed a huge tumor of the left lower lung lobe, and invasion to the aortic wall was suspected. Bronchoscopic examination was performed, revealing squamous cell carcinoma with a programmed death ligand 1 expression level of 90%. The clinical stage was T4N0M0 stage 3A. After neoadjuvant chemotherapy and radiotherapy, we performed one-stage surgery with the patient in the right lateral decubitus position and the left inguinal region exposed for femoral vessel isolation. Posterolateral thoracotomy was performed with making a latissimus dorsi muscle flap. The pulmonary artery, vein, and left lower bronchus were cut with a stapler. After hilar isolation, we evaluated the involvement of the descending aorta and marked the area of the involved aortic wall by a surgical clip. Using the left femoral artery approach, a GORE TAG conformable thoracic stent graft was delivered to the descending aorta. After thoracic aortic endografting, the involved aortic wall was resected and the left lower lobe of the lung and resected aortic wall were resected en bloc. The adventitial defect was covered by the latissimus dorsi muscle flap. The operating time was 474 min, and the blood loss volume was 330 mL. The postoperative pathological diagnosis was adenocarcinoma with an epidermal growth factor receptor mutation of exon 19 deletion. The residual viable tumor was 7 mm in diameter and close to the resected aortic wall. The patient's postoperative course was uneventful. Five days after surgery, chest contrast-enhanced computed tomography revealed no endoleak or stent migration. Three months after surgery, he was alive with neither recurrence nor stent graft-related complications. CONCLUSIONS: One-stage surgery involving combined resection of lung cancer and the thoracic aortic wall with simultaneous thoracic aortic endografting in the right lateral decubitus position with the left inguinal region exposed is safe and acceptable.

A survey of carboplatin desensitization therapy in Japan: A multicenter retrospective study.

INTRODUCTION: Hypersensitivity reactions (HSRs) to chemotherapy are serious adverse events associated with cancer drug therapy and can occur with any antitumor drug. This study investigated the safety and efficacy of carboplatin desensitization therapy in Japan and established a method for treating carboplatin HSRs. METHODS: Patients diagnosed with gynecological (ovarian, endometrial, or cervical) cancers who underwent carboplatin desensitization therapy between 2016 and 2020 at the Gynecologic Cancer Study Group of Japan Clinical Oncology Group were included. The carboplatin desensitization therapy at each institution and the implementation cases were registered in an online case report form. RESULTS: This retrospective study enrolled 136 patients (ovarian, 108; endometrial, 17; and cervical cancer, 11). Pre-existing allergies were present in 37 (27.2%) patients, and 32 (23.5%) patients exhibited prodromal symptoms during treatment before HSR onset. Erythema was the most common symptom at HSR onset, affecting 93 (68.4%) patients, followed by itching in 72 (52.9%) patients and decreased oxygen saturation in 43 (31.6%) patients. Loss of consciousness occurred in three (2.2%) patients. The most common timing of HSR onset was during the first recurrence treatment (47%). The mean total carboplatin dose until HSR onset was 7331 (2620-18,282) mg, and the mean number of doses was 14 (4-63). Desensitization treatment was completed in 75% of cases, and breakthrough HSRs occurred in 25% (34/136). No deaths occurred in the study cohort. The risk factors for HSRs were not identified. CONCLUSION: Although carboplatin desensitization therapy has high success rates in Japan, erythema and pruritus are important HSRs to consider.

Microscopic thymoma with a thymic cyst that enlarged over a 2-year period.

An 81-year-old woman was referred to our hospital because of right lung cancer. She underwent right upper lobectomy. Pathological examination revealed stage 1A adenocarcinoma. Four months postoperatively, chest computed tomography showed a small nodule with a diameter of 6 mm at the anterior mediastinum. After 2 years, the nodule had increased to 13 mm. To confirm the diagnosis and treat the mediastinal tumor, we resected the tumor and surrounding thymic tissue by a left robotic thoracic approach, considering the adhesion in the right thoracic cavity after right pulmonary resection. The operating time was 43 min. The patient had a favorable postoperative course and was discharged 3 days after surgery. Pathological examination revealed microscopic thymoma with a diameter of 400 µm very close to a thymic cyst. Microscopic thymoma can occur around a thymic cyst without myasthenia gravis, and the thymic tissue around the anterior mediastinal cyst should be resected.

Double polytetrafluoroethylene patch repair for diaphragmatic defect caused by diaphragmatic rupture following diaphragmatic resection with endostapler.

A 41-year-old man developed phrenic nerve palsy after the resection of anterior mediastinal tumor, who underwent diaphragmatic resection with an endostapler. After the surgery, the surgical stump ruptured, resulting in a large diaphragmatic defect with the liver prolapsing into the thoracic cavity. Then, the diaphragmatic defect was closed with a polytetrafluoroethylene (PTFE) patch. The diaphragm was reconstructed using a second PTFE patch overlaying the diaphragmatic defect that had been closed by the first PTFE patch, because solely patching the diaphragmatic defect had a risk of recurrence of diaphragmatic elevation due to remaining original diaphragm and the presence of phrenic nerve palsy. The second PTFE patch was fixed to the lower ribs by non-absorbable suture. The postoperative course was favorable. After 3 months, his symptoms and pulmonary function improved. We underwent double PTFE patch repair in a patient with both huge diaphragmatic defect and phrenic nerve palsy.

Prolonged second stage of labor in delivery using epidural analgesia is a risk factor for postpartum urinary retention.

AIM: To determine the postpartum urinary retention rate and risk factors after delivery using epidural analgesia. METHODS: This single-center retrospective study targeted 341 women who gave birth after at least 37 weeks of gestation from April to August 2021; from this cohort, 208 patients were examined. The postpartum urinary retention rate was compared between the no epidural analgesia group (n = 107) and epidural analgesia group (n = 101). Subsequently, risk factors for postpartum urinary retention were investigated in the epidural analgesia group. RESULTS: After adjustment by propensity score matching for age, body mass index, being primiparous, and labor induction as covariates, the analysis of the incidence of postpartum urinary retention revealed that the epidural analgesia group exhibited a significantly higher postpartum urinary retention rate than the no epidural analgesia group (30% vs. 11%, p = 0.02). The investigation results regarding risk factors for postpartum urinary retention in the epidural analgesia group obtained through a univariate analysis showed that being primiparous and having a prolonged second stage of labor were significantly correlated with postpartum urinary retention. Multivariate analysis indicated that a prolonged second stage of labor was an independent risk factor for postpartum urinary retention (p = 0.03; odds ratio: 3.18; 95% confidence interval: 1.08-9.77). All patients recovered from postpartum urinary retention by day 4. CONCLUSIONS: The postpartum urinary retention rate after delivery using epidural analgesia was 25.7%. In the case of epidural analgesia deliveries, a prolonged second stage of labor was an independent risk factor for postpartum urinary retention.