Rapamycin prevents cyclophosphamide-induced ovarian follicular loss and potentially inhibits tumour proliferation in a breast cancer xenograft mouse model.

STUDY QUESTION: To what extent and via what mechanism does the concomitant administration of rapamycin (a follicle activation pathway inhibitor and antitumour agent) and cyclophosphamide (a highly toxic ovarian anticancer agent) prevent cyclophosphamide-induced ovarian reserve loss and inhibit tumour proliferation in a breast cancer xenograft mouse model? SUMMARY ANSWER: Daily concomitant administration of rapamycin and a cyclic regimen of cyclophosphamide, which has sufficient antitumour effects as a single agent, suppressed cyclophosphamide-induced primordial follicle loss by inhibiting primordial follicle activation in a breast cancer xenograft mouse model, suggesting the potential of an additive inhibitory effect against tumour proliferation. WHAT IS KNOWN ALREADY: Cyclophosphamide stimulates primordial follicles by activating the mammalian target of the rapamycin (mTOR) pathway, resulting in the accumulation of primary follicles, most of which undergo apoptosis. Rapamycin, an mTOR inhibitor, regulates primordial follicle activation and exhibits potential inhibitory effects against breast cancer cell proliferation. STUDY DESIGN, SIZE, DURATION: To assess ovarian follicular apoptosis, 3 weeks after administering breast cancer cells, 8-week-old mice were randomized into three treatment groups: control, cyclophosphamide, and cyclophosphamide + rapamycin (Cy + Rap) (n = 5 or 6 mice/group). Mice were treated with rapamycin or vehicle control for 1 week, followed by a single dose of cyclophosphamide or vehicle control. Subsequently, the ovaries were resected 24 h after cyclophosphamide administration (short-term treatment groups). To evaluate follicle abundance and the mTOR pathway in ovaries, as well as the antitumour effects and impact on the mTOR pathway in tumours, 8-week-old xenograft breast cancer transplanted mice were randomized into three treatment groups: vehicle control, Cy, and Cy + Rap (n = 6 or 7 mice/group). Rapamycin (5 mg/kg) or the vehicle was administered daily for 29 days. Cyclophosphamide (120 mg/kg) or the vehicle was administered thrice weekly (long-term treatment groups). The tumour diameter was measured weekly. Seven days after the last cyclophosphamide treatment, the ovaries were harvested, fixed, and sectioned (for follicle counting) or frozen (for further analysis). Similarly, the tumours were resected and fixed or frozen. PARTICIPANTS/MATERIALS, SETTING, METHODS: Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) was performed to examine ovarian follicular apoptosis in the short-term treatment groups. All subsequent experiments were conducted in the long-term treatment groups. Tumour growth was evaluated using the tumour volume index. The tumour volume index indicates the relative volume, compared to the volume 3 weeks after tumour cell injection (at treatment initiation) set to 100%. Tumour cell proliferation was evaluated by Ki-67 immunostaining. Activation of the mTOR pathway in tumours was assessed using the protein extracts from tumours and analysed by western blotting. Haematoxylin and eosin staining of ovaries was used to perform differential follicle counts for primordial, primary, secondary, antral, and atretic follicles. Activation of the mTOR pathway in ovaries was assessed using protein extracts from whole ovaries and analysed by western blotting. Localization of mTOR pathway activation within ovaries was assessed by performing anti-phospho-S6 kinase (downstream of mTOR pathway) immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: Ovaries of the short-term treatment groups were resected 24 h after cyclophosphamide administration and subjected to TUNEL staining of apoptotic cells. No TUNEL-positive primordial follicles were detected in the control, Cy, and Cy + Rap groups. Conversely, many granulosa cells of growing follicles were TUNEL positive in the Cy group but negative in the control and Cy + Rap groups. All subsequent experimental results were obtained from the long-term treatment groups. The tumour volume index stabilized at a mean of 160-200% in the Cy group and 130% in the Cy + Rap group throughout the treatment period. In contrast, tumours in the vehicle control group grew continuously with a mean tumour volume index of 600%, significantly greater than that of the two treatment groups. Based on the western blot analysis of tumours, the mTOR pathway was activated in the vehicle control group and downregulated in the Cy + Rap group when compared with the control and Cy groups. Ki-67 immunostaining of tumours showed significant inhibition of cell proliferation in the Cy + Rap group when compared with that in the control and Cy groups. The ovarian follicle count revealed that the Cy group had significantly fewer primordial follicles (P < 0.001) than the control group, whereas the Cy + Rap group had significantly higher number of primordial follicles (P < 0.001, 2.5 times) than the Cy group. The ratio of primary to primordial follicles was twice as high in the Cy group than in the control group; however, no significant difference was observed between the control group and the Cy + Rap group. Western blot analysis of ovaries revealed that the mTOR pathway was activated by cyclophosphamide and inhibited by rapamycin. The phospho-S6 kinase (pS6K)-positive primordial follicle rate was 2.7 times higher in the Cy group than in the control group. However, this effect was suppressed to a level similar to the control group in the Cy + Rap group. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: The combinatorial treatment of breast cancer tumours with rapamycin and cyclophosphamide elicited inhibitory effects on cell proliferative potential compared to cyclophosphamide monotherapy. However, no statistically significant additive effect was observed on tumour volume. Thus, the beneficial antitumour effect afforded by rapamycin administration on breast cancer could not be definitively proven. Although rapamycin has ovarian-protective effects, it does not fully counteract the ovarian toxicity of cyclophosphamide. Nevertheless, rapamycin is advantageous as an ovarian protective agent as it can be used in combination with other ovarian protective agents, such as hormonal therapy. Hence, in combination with other agents, mTOR inhibitors may be sufficiently ovario-protective against high-dose and cyclic cyclophosphamide regimens. WIDER IMPLICATIONS OF THE FINDINGS: Compared with a cyclic cyclophosphamide regimen that replicates human clinical practice under breast cancer-bearing conditions, the combination with rapamycin mitigates the ovarian follicle loss of cyclophosphamide without interfering with the anticipated antitumour effects. Hence, rapamycin may represent a new non-invasive treatment option for cyclophosphamide-induced ovarian dysfunction in breast cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This work was not financially supported. The authors declare that they have no conflict of interest.

Comparison of postoperative adjuvant platinum-based chemotherapy and no further therapy after radical surgery in intermediate-risk early-stage cervical cancer.

OBJECTIVE: To identify a relatively high-risk population in postoperative intermediate-risk cervical cancer and evaluate the effect of platinum-based adjuvant chemotherapy (CT). METHODS: We retrospectively reviewed the medical records of patients with stage IA2-IIA cervical cancer who had been treated with radical hysterectomy and pelvic lymphadenectomy and classified as the intermediate-risk group for recurrence by postoperative pathological examination from January 2007 to December 2018 at 3 medical centers in Japan. First, patients with intermediate-risk were stratified by histological type and the number of intermediate-risk factors (IRF; large tumor diameter, lymph vascular space invasion, and deep cervical stromal invasion) and then divided into 2 groups: high and low-risk population (estimated 5-year recurrence-free survival [RFS] rate with no further therapy [NFT] <90% and ≥90%, respectively). Second, the efficacy of CT for the high-risk population was evaluated by comparing RFS and overall survival (OS) between the patients receiving CT and those with NFT. RESULTS: In total, 133 patients were included in the analysis. Among patients with squamous cell carcinoma (SCC) with all IRF or those with non-SCC with 2 to 3 IRF, the 5-year estimated RFS was <90% when treated with NFT. In this population, adjuvant CT was significantly superior to NFT regarding RFS (log-rank, p=0.014), although there was no statistical difference in OS. CONCLUSION: Patients with SCC with all 3 IRFs and those with non-SCC with 2 to 3 IRFs were at high risk for recurrence. Adjuvant CT is a valid treatment option for these populations.

Borg's exertion scale did not coincide with ventilatory anaerobic threshold in atrial fibrillation patients with restored sinus rhythm after ablation.

The determination of precise exercise intensity is essential for effective exercise rehabilitation. The Borg rating of perceived exertion category ratio (CR) scale is utilized to prescribe an appropriate level of exertion intensity. A Borg CR of approximately 13 coincides with the ventilatory aerobic threshold (VAT). Patients with atrial fibrillation (AF) exhibit various symptoms. We hypothesized that the workload at Borg CR13 (Borg CR13-Watt) differs from the workload at the VAT level (VAT-Watt) in AF patients with restored sinus rhythm (SR) following ablation. Accordingly, the relationship between Borg CR13-Watt and VAT-Watt was studied in patients with restored SR. Cardiopulmonary exercise testing (CPET) was performed at 101±88 days after ablation in 150 patients using a bicycle ergometer. No adverse events were observed during CPET. Borg CR13-Watt was significantly higher than VAT-Watt (67.2±27.8 Watt vs. 54.7±17.6 Watt, P<0.0001). Borg CR13-Watt showed significant linear regression with VAT-Watt (regression coefficient, 0.49, P<0.01; correlation coefficient, 0.80, P<0.01). Higher Borg CR13-Watt was associated with greater differences between Borg CR13-Watt and VAT-Watt (ΔWatt). The Bland-Altman plot showed nonconcordance between the two. Male sex, use of antiarrhythmic drugs, and smoking had contributed to the increased ΔWatt. Duration from ablation to time of CPET did not correlate with ΔWatt. Therefore, Borg CR13-Watt did not coincide with VAT-Watt in patients with restored SR. Higher Borg CR13-Watt was associated with greater ΔWatt. Prescribing exertion intensity as determined solely by perceived exertion is inadequate. CPET is required to determine the precise exercise intensity in AF patients with restored SR after ablation.

Successful ovarian tissue cryopreservation with transvaginal natural orifice transluminal endoscopic surgery: A case report.

Chemotherapy and radiation therapy can cause gonadal dysfunction in women of reproductive age. Ovarian tissue cryopreservation is performed to restore fertility by allowing transplantation of the patient's frozen-thawed ovarian tissue or through future in vitro maturation and in vitro fertilization of frozen-thawed oocytes. Herein, we describe our initial experience with vaginal natural orifice transluminal endoscopic surgery for ovarian tissue preservation in a young woman with malignant tumor. A 23-year-old woman with anaplastic lymphoma kinase-positive malignant lymphoma was scheduled for hematopoietic stem cell transplantation after experiencing relapse following R-cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy. Ovarian tissue cryopreservation was selected as only MII2 oocytes were collected. Vaginal natural orifice transluminal endoscopic surgery was performed to excise the left ovary. Ovarian tissues were frozen using the vitrification method. The operative time was 37 min, and blood loss was minimal. Pathological examination revealed no metastatic findings of malignant lymphoma and no thermal damage to the ovarian tissue due to bipolar disorder. The patient was discharged on the first day postoperatively, and her postoperative course was uneventful. The vaginal natural orifice transluminal endoscopic surgery technique can provide a safe and effective alternative to laparoscopy or laparotomy for the cryopreservation of ovarian tissue in young patients with cancer. We believe this method has potential application in sexually mature female cancer survivors.

Ovarian tissue cryopreservation with vaginal natural orifice transluminal endoscopic surgeryChemotherapy and radiotherapy can affect a woman's ability to have children by reducing ovarian function. This can make it hard to conceive even with fertility treatments. Freezing healthy ovaries before these treatments can help restore fertility. This can be done by freezing and later transplanting ovarian tissue or by fertilizing frozen eggs in a lab. Traditional surgery to remove ovaries can cause cosmetic issues and pain. But now, a new method called vaginal spontaneous opening transperitoneal endoscopic surgery is becoming more common. This surgery is less invasive, quicker, and causes less bleeding. We recently used this method to preserve ovarian tissue in young women with cancer. The surgery was successful with minimal complications. This new approach could offer a safer option for preserving fertility in female cancer survivors.

Effectiveness of an articulating laparoscopic needle holder for cesarean scar defect repair.

AIM: To evaluate the efficacy of an articulating laparoscopic needle holder in laparoscopic surgery for cesarean scar defect. METHODS: We performed a retrospective case-control study at the Shiga University of Medical Science. Patients who underwent laparoscopic uterine scar repair were divided into an articulating laparoscopic needle holder (ArtiSential®) group and a rigid needle holder (conventional) group to compare the suture and total operative times. Uterine myometrial suturing involves a double-layer interrupted suture, including a modified Gambee suture for the first layer. We measured the residual myometrial thickness using magnetic resonance imaging preoperatively and at 3 months postoperatively. RESULTS: Both groups comprised 10 patients each. The time per stitch for the first and second layers was significantly shorter in the ArtiSential group than in the conventional group (median 208 s vs. 403 s, p < 0.0001 and median 17 s vs. 29 s; p < 0.0001, respectively). The total operating time was significantly shorter in the ArtiSential group (mean 188 min vs. 240 min, p = 0.0015). The postoperative residual myometrial thickness (mean 9.1 mm in the ArtiSential group and 9.6 mm in the conventional group) was significantly higher than the preoperative residual myometrial thickness (mean 1.6 mm in the ArtiSential group and 1.6 mm in the conventional group) (p < 0.0001 in both groups). CONCLUSIONS: An articulating needle holder is useful in laparoscopic surgery for cesarean scar defect, especially when a modified Gambee suture is required.

[A Case of the Huge GIST in the Transverse Colon Mesentery with Intra-Tumoral Hemorrhage and Jejunal Infiltration].

A 38-year-old woman was admitted to our hospital due to severe anemia. CT showed a 13×12 cm tumor with moderately enhanced wall thickening in the right upper abdomen. The huge tumor located adjacent to the jejunum and compressed the right transverse colon. Hemorrhagic necrosis and air were observed within the tumor, suspecting tumor penetration into the jejunum. The patient was diagnosed with abdominal GIST with jejunal infiltration. Laparotomy revealed a 13× 11 cm solid mass with intra-tumoral hemorrhage and invasion into the jejunum, located in the transverse mesocolon. Tumor resection combined with partial jejunectomy and transverse colectomy were performed. Immunohistochemical findings of the resected specimen was positive for c-kit and DOG-1, and the MIB-1 positive rate was 10%. Three weeks after the operation, re-anastomosis was performed due to transverse colon anastomotic stricture. She was discharged 45 days after first operation. Currently, 9 months after the operation, patient has been prescribed imatinib and is alive without recurrence.

[Results of Watch and Wait after Chemoradiotherapy for Locally Advanced Rectal Cancer].

BACKGROUND: Watch and wait(W & W)for rectal cancer after chemoradiotherapy(CRT)is attracting attention. PURPOSE: To examine regimens and indications from the results of follow-up of cases undergoing W & W in our department. MATERIALS AND METHODS: CRT(SOX therapy 2-5 cycles, 45 Gy)was performed on patients with lower rectal cancer over a period of 2016 to 2020, and 7 patients with clinical complete response(cCR)were followed up. RESULTS: With a median follow-up of 33 months(10-74), 4 of 7 patients(57.1%)remained in cCR. Two patients had local relapse more than a year after the start of treatment, were able to undergo salvage surgery, and are alive after surgery. Patients with lateral lymph node metastasis before CRT had para-aortic lymph node metastasis at 8 months. CONCLUSIONS: Patients with maintained cCR were those with localized, node-negative disease. On the other hand, in patients with lymph node metastasis, including lateral metastasis, it was not possible to perform salvage surgery due to distant metastasis. Careful case selection and follow-up are necessary in the future.

Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy.

The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.

Inhibition of PRMT5/MEP50 Arginine Methyltransferase Activity Causes Cancer Vulnerability in NDRG2low Adult T-Cell Leukemia/Lymphoma.

N-myc downstream-regulated gene 2 (NDRG2), which is a tumour suppressor, is frequently lost in many types of tumours, including adult T-cell leukaemia/lymphoma (ATL). The downregulation of NDRG2 expression is involved in tumour progression through the aberrant phosphorylation of several important signalling molecules. We observed that the downregulation of NDRG2 induced the translocation of protein arginine methyltransferase 5 (PRMT5) from the nucleus to the cytoplasm via the increased phosphorylation of PRMT5 at Serine 335. In NDRG2low ATL, cytoplasmic PRMT5 enhanced HSP90A chaperone activity via arginine methylation, leading to tumour progression and the maintenance of oncogenic client proteins. Therefore, we examined whether the inhibition of PRMT5 activity is a drug target in NDRG2low tumours. The knockdown of PRMT5 and binding partner methylsome protein 50 (MEP50) expression significantly demonstrated the suppression of cell proliferation via the degradation of AKT and NEMO in NDRG2low ATL cells, whereas NDRG2-expressing cells did not impair the stability of client proteins. We suggest that the relationship between PRMT5/MEP50 and the downregulation of NDRG2 may exhibit a novel vulnerability and a therapeutic target. Treatment with the PRMT5-specific inhibitors CMP5 and HLCL61 was more sensitive in NDRG2low cancer cells than in NDRG2-expressing cells via the inhibition of HSP90 arginine methylation, along with the degradation of client proteins. Thus, interference with PRMT5 activity has become a feasible and effective strategy for promoting cancer vulnerability in NDRG2low ATL.

Management of Pregnant Women with Mental Disorders Requires Attention to Gestational Diabetes Mellitus.

Background: Psychiatric interventions may be required during pregnancy. In the aspect of the management of psychiatric symptoms and the consideration of the need for pharmacotherapy, possibly to manage the effects on the fetus, pregnant women with mental disorders are considered high risk as other physical illnesses. Objective: We investigated the characteristics of pregnant women with psychiatric disorders compared with high-risk pregnant women with physical illnesses at our university hospital and the effects of psychotropic drug use on pregnant women with mental disorders and their children. Materials and Methods: In a multivariate analysis of 1282 pregnant women, excluding those with multiple pregnancies who gave birth at our hospital between January 2017 and the end of December 2019, we evaluated the effects of mental disorders and the use of psychotropic drugs throughout at least the third trimester up to the day of delivery on obstetric complications and infants. All data were collected retrospectively. Results: Ninety-nine pregnant women had mental disorders and 62 took psychotropic drugs. Among multiple factors, pregnant women with mental disorders were associated with significantly higher rates of smoking and gestational diabetes mellitus (GDM) and significantly lower child abnormalities. The cause or effect was difficult to determine; however, the use of antipsychotics or antidepressants was also significantly associated with GDM, while psychotropic use was not related to any of the other factors investigated in this study. Conclusions: Attention to GDM might be important in the management of pregnant women with mental disorders.

Cases of pleural effusion possibly due to clinical pleuroperitoneal communication in the perioperative period of emergency gynecologic surgery: Case series and literature review.

Pleuroperitoneal communication poses a respiratory failure risk due to pleural fluid accumulation with thoracic migration of ascites. Here, we discuss the following cases: Case 1: A woman was diagnosed with a ruptured ovarian tumor with right pleural fluid and ascites, without respiratory failure. Ovarian cystectomy was performed with inadequate removal of ascites. Postoperatively, respiratory failure occurred, and thoracentesis detected pleural fluid resembling ascites. Case 2: A woman was diagnosed with a ruptured ectopic pregnancy with right pleural fluid and ascites without respiratory failure. A diagnosis of clinical pleuroperitoneal communication was considered based on computed tomography findings. During laparoscopic salpingectomy, high-pressure ventilation was performed to push the pleural fluid back into the abdominal cavity; a negative-pressure drain was inserted, and the ascites was completely removed. Postoperative radiography revealed the absence of pleural fluid. Therefore, a preoperative diagnosis of clinical pleuroperitoneal communication and appropriate intraoperative techniques can prevent postoperative respiratory failure.

Infection of tumor cells with Salmonella typhimurium mimics immunogenic cell death and elicits tumor-specific immune responses.

Some properties of Salmonella-infected cells overlap with immunogenic cell death. In this study, we demonstrated that intracellular infection of melanoma with Salmonella typhimurium induced high immunogenicity in melanoma cells, leading to antitumor effects with melanoma-antigen-specific T-cell responses. Murine B16F10 melanoma cells were infected with tdTomato-expressing attenuated S. typhimurium (VNP20009; VNP-tdT), triggering massive cell vacuolization. VNP-tdT-infected B16F10 cells were phagocytosed efficiently, which induced the activation of antigen-presenting cells with CD86 expression in vitro. Subcutaneous coimplantation of uninfected and VNP-tdT-infected B16F10 cells into C57BL/6 mice significantly suppressed tumor growth compared with the implantation of uninfected B16F10 cells alone. Inoculation of mice with VNP-tdT-infected B16F10 cells elicited the proliferation of melanoma-antigen (gp100)-specific T cells, and it protected the mice from the second tumor challenge of uninfected B16F10 cells. These results suggest that Salmonella-infected tumor cells acquire effective adjuvanticity, leading to ideal antitumor immune responses.

An ampullary adenoma presenting with jaundice caused by duodenal intussusception: a case report.

BACKGROUND: Ampullary adenomas are premalignant lesions. However, biliary obstruction causing jaundice is rare. Duodenal intussusception secondary to an ampullary adenoma rarely occurs because of the fixed position of the duodenum in the retroperitoneum. Herein, we have described a rare case of ampullary adenoma with jaundice caused by duodenal intussusception. CASE PRESENTATION: A 40-year-old woman presenting with vomiting and yellowish discoloration of the skin was admitted to another hospital. The patient had experienced recurrent epigastric pain and vomiting for the past 18 months. Blood test results showed elevated levels of bilirubin (3.9 mg/dL), and abdominal computed tomography (CT) showed a 60-mm hypovascular mass in the third part of the duodenum and a left lateral shift of the dilated common bile duct. The patient was referred to our hospital for further evaluation. She recovered from hyperbilirubinemia spontaneously (levels of bilirubin, 1.0 mg/dL), and the CT showed a tumor shift from the third part of the duodenum to the second part and improvement of the dilated common bile duct. Hypotonic duodenography revealed a tumor that moved easily from the second to the third portion of the patient's position. Upper gastrointestinal endoscopy revealed a large papillary tumor occupying the second part of the duodenum, which was diagnosed as an adenoma through biopsy. The possibility of malignancy could not be negated owing to the presence of jaundice and an elevated carbohydrate antigen 19-9 level (76.0 U/mL). Pancreaticoduodenectomy was performed. The resected specimen showed a 60 × 40 × 40-mm pedunculated ampullary mass with submucosal elongation. The pathological examination indicated that the ampullary tumor was a high-grade intestinal adenoma. The postoperative course was uneventful, and the patient was discharged 26 days postoperatively. CONCLUSIONS: This report describes a rare case of a patient with an ampullary adenoma presenting with jaundice resulting from duodenal intussusception. Owing to the possibility of a postoperative cancer diagnosis which may have caused the biliary obstruction and the difficulty in making an accurate preoperative diagnosis, it is imperative to choose the appropriate surgical procedure such as a pancreaticoduodenectomy.

An Analysis of Delayed Bleeding in Cases of Colorectal Endoscopic Submucosal Dissection Due to Types of Direct Oral Anticoagulants in Japan.

BACKGROUND & AIMS: Reported rates of delayed bleeding (DB) after endoscopic resection using direct oral anticoagulants (DOACs) are high and heterogeneous. This large-scale multicenter study analyzed cases of DB after colorectal endoscopic submucosal dissection related to various types of DOACs in Japan (the ABCD-J study) with those associated with warfarin. METHODS: We retrospectively reviewed 1019 lesions in patients treated with DOACs and 459 lesions in patients treated with warfarin among 34,455 endoscopic submucosal dissection cases from 47 Japanese institutions between 2012 and 2021. The DB rate (DBR) with each DOAC was compared with that with warfarin. Risk factors for DB in patients treated with DOACs or warfarin were also investigated. RESULTS: The mean tumor sizes in the DOAC and warfarin groups were 29.6 ± 14.0 and 30.3 ± 16.4 mm, respectively. In the DOAC group, the DBR with dabigatran (18.26%) was significantly higher than that with apixaban (10.08%, P = .029), edoxaban (7.73%, P = .001), and rivaroxaban (7.21%, P < .001). Only rivaroxaban showed a significantly lower DBR than warfarin (11.76%, P = .033). In the multivariate analysis, heparin bridging therapy (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.27-3.73, P = .005), rectal location (2.01, 1.28-3.16, P = .002), and procedure time ≥55 minutes (2.43, 1.49-3.95, P < .001) were significant risk factors for DB in the DOAC group. The DB risk in the DOAC group (OR, (95% CI)) was 2.13 (1.30-3.50) and 4.53 (2.52-8.15) for 1 and 2 significant risk factors, respectively. CONCLUSIONS: Dabigatran was associated with a higher DBR than other DOACs, and only rivaroxaban was associated with a significantly lower DBR than warfarin.

Humanized Anti-Carcinoembryonic Antigen Antibodies Brightly Target and Label Gastric Cancer in Orthotopic Mouse Models.

INTRODUCTION: Gastric cancer poses a major therapeutic challenge. Improved visualization of tumor margins at the time of gastrectomy with fluorescent tumor-specific antibodies could improve outcomes. The present report demonstrates the potential of targeting gastric cancer with a humanized anti-carcinoembryonic antigen (CEA) antibody in orthotopic mouse models. METHODS: MKN45 cells were injected subcutaneously into nude mice to establish xenograft models. Tumor fragments collected from subcutaneous models were then implanted into the greater curvature of the stomach to establish orthotopic models. For tumor labeling, a humanized anti-CEA antibody (M5A) and IgG as a control, were conjugated with the near-infrared dye IRDye800CW. Time (24-72 h) and dose (50-100 µg) response curves were performed in subcutaneous models. Orthotopic models received 50 µg of M5A-IR800 or 50 µg IgG-IR800 as a control and were imaged after 72 h. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System. RESULTS: In subcutaneous models, tumor to background ratios (TBRs) reached 8.85 at 72 h. Median TBRs of orthotopic model primary tumors were 6.25 (interquartile range [IQR] 6.03-7.12) for M5A-IR800 compared to 0.42 (IQR 0.38-0.54) for control. Abdominal wall metastasis median TBRs were 13.52 (IQR 12.79-13.76) for M5A-IR800 and 3.19 (IQR 2.65-3.73) for the control. Immunohistochemistry confirmed CEA expression within tumors. CONCLUSIONS: Humanized anti-CEA antibodies conjugated to near-infrared dyes provide specific labeling of gastric cancers in mouse models. Orthotopic models demonstrated bright and specific labeling with TBRs greater than ten times that of control. This tumor-specific fluorescent antibody is a promising potential clinical tool for improving visualization of gastric cancer margins at time of surgical resection.

Short-term and long-term outcomes of submucosal dissection for residual or recurrent colorectal tumors after endoscopic resection: Analysis of a multicenter prospective study.

OBJECTIVES: We previously demonstrated that a favorable long-term prognosis indicated that endoscopic submucosal dissection (ESD) could be the standard treatment for large colorectal epithelial neoplasms, but the usefulness of ESD for local residual or recurrent tumors with submucosal fibrosis has not been fully demonstrated. The aim of the present study was to assess the usefulness of ESD for local residual or recurrent colorectal tumors. METHODS: We conducted a nationwide multicenter prospective study to evaluate the outcomes of ESD for colorectal tumors. In this post hoc analysis, a total of 54 local residual or recurrent colorectal tumors in 54 patients were included, and we analyzed the short-term and long-term outcomes of ESD for these lesions. RESULTS: The median size of the lesions was 16.0 (interquartile range [IQR] 11-25) mm. ESD was completed in 53 cases (98.1%) with a median procedure time of 65.0 min, but it was discontinued in one case because of submucosal cancer invasion. En bloc resection was achieved in 52 cases (96.3%), whereas R0 resection was achieved in 45 cases (83.3%). Intraoperative perforation was observed in four cases (7.4%) and delayed perforation in one (1.9%), but all cases could be managed conservatively. Delayed bleeding was not observed. There were no significant differences in short-term outcomes between the rectal and colonic lesions. There was no recurrence of the tumor during the median follow-up period of 60 (IQR 50-64) months. CONCLUSION: An analysis of our multicenter prospective study suggests that ESD is an effective salvage management for local residual or recurrent colorectal lesions.

Small Intestinal Arteriovenous Malformation Treated by Double-balloon Endoscopy: A Case Report.

A 42-year-old man was referred to our hospital because of anemia. The patient underwent gastroscopy and colonoscopy, but no bleeding site was detected. Abdominal contrast-enhanced computed tomography (CT) showed vascular dilatation along the wall of the small intestine. Small bowel capsule endoscopy and antegrade double-balloon endoscopy (DBE) were performed, and the patient was diagnosed with a small intestinal arteriovenous malformation (AVM). The AVM was clipped using DBE. After clipping, abdominal contrast-enhanced CT and small bowel angiography revealed the disappearance of the AVM. DBE may be a viable therapeutic option, helping avoid surgery and its associated risks.

Erratum: Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.

[This corrects the article DOI: 10.1016/j.omto.2023.100728.].

Ligand-based, piggyBac-engineered CAR-T cells targeting EGFR are safe and effective against non-small cell lung cancers.

Epidermal growth factor receptor (EGFR) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), and in some somatic cells at a limited level, rendering it an attractive antitumor target. In this study, we engineered chimeric antigen receptor (CAR)-T cells using the piggyBac transposon system, autologous artificial antigen-presenting cells, and natural ligands of EGFR. We showed that this approach yielded CAR-T cells with favorable phenotypes and CAR positivity. They exhibited potent antitumor activity against NSCLC both in vitro and in vivo. When administered to tumor-bearing mice and non-tumor-bearing cynomolgus macaques, they did not elicit toxicity despite their cross-reactivity to both murine and simian EGFRs. In total we tested three ligands and found that the CAR candidate with the highest affinity consistently displayed greater potency without adverse events. Taken together, our results demonstrate the feasibility and safety of targeting EGFR-expressing NSCLCs using ligand-based, piggyBac-engineered CAR-T cells. Our data also show that lowering the affinity of CAR molecules is not always beneficial.

Impact of administering umbilical cord-derived mesenchymal stem cells to cynomolgus monkeys with endometriosis.

Purpose: This study aimed to explore whether umbilical cord-derived mesenchymal stem cells (UC-MSCs) could be used as a therapeutic resource for endometriosis. Methods: Of seven cynomolgus monkeys with endometriosis, five were administered UC-MSCs (intervention group) and two were administered saline (control group). First, intravenous US-MSC treatment was administered for three months. Second, weekly intravenous US-MSC administration combined with monthly intraperitoneal US-MSC administration was conducted for 3 months. Finally, weekly intraperitoneal US-MSC administration was conducted for 3 months. The dose of UC-MSCs was set to 2 × 106 cells/kg for all administration routes. Laparoscopic findings and serum cancer antigen 125 (CA125) levels were also evaluated. The Revised American Society for Reproductive Medicine classification was used for laparoscopic evaluation. Results: Laparoscopic findings showed exacerbation of endometriosis after intraperitoneal UC-MSC administration, although no changes were observed in the control group. Intravenous UC-MSC administration decreased the level of CA125 in all monkeys; however, the difference was not significant. Intraperitoneal UC-MSC administration significantly exacerbated endometriosis compared with intravenous administration (p = 0.02). Conclusions: This study revealed that intraperitoneal UC-MSC administration exacerbates endometriosis in a nonhuman primate model of the disease.