Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade.

BACKGROUND: The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs. METHODS: We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models. RESULTS: High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs. CONCLUSION: Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

Efficacy and safety of a novel temperature-controlled catheter for cavotricuspid isthmus ablation.

BACKGROUND: Maintaining an adequate temperature at the target site is essential for effective ablation. We hypothesized that a tissue temperature-controlled (T-Con) catheter for cavotricuspid isthmus (CTI) ablation could improve the procedural ablation parameters. PURPOSE: To evaluate the efficacy and safety of the T-Con (DiamondTemp™) catheter for CTI ablation compared with non-irrigation (Non-Irri) and irrigation (Irri) catheters. METHODS: We analyzed 150 patients who underwent prophylactic CTI ablation combined with pulmonary vein isolation. The Non-Irri, Irri, and T-Con catheter groups comprised 50 patients each, and the ablation procedural parameters and complications were compared between these groups. RESULTS: There were no significant differences in clinical background characteristics among the three groups. The Kruskal-Wallis and post hoc tests demonstrated that the T-Con group showed the lowest total radiofrequency energy delivery time among the three groups (median [25 and 75 percentiles]: 340 [209, 357], 147 [100, 199], and 83 [61, 109] s, respectively in the Non-Irri, Irri, and T-Con groups; T-Con versus Non-Irri, p < .01; T-Con versus Irri, p < .01). The total procedural time and acute reconnection rate in the T-Con group (264 s and 4%, respectively) were lower than those in the Non-Irri group (438 s and 24%) but were similar to those in the Irri group (268 s and 6%). No significant complications were observed in any group. CONCLUSIONS: The T-Con catheter achieved a short energy delivery time and a low acute reconnection rate, indicating its potential as an alternative catheter for CTI ablation.

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.

Ki-67 distribution, α-methylacyl-CoA racemase (AMACR) expression and mucin phenotypes are associated with non-polypoid growth in ulcerative colitis-associated neoplasia.

AIMS: Ulcerative colitis-associated neoplasia (UCAN) is characterised by multifocal tumourigenesis. A wide range of metachronous lesions have been reported to occur after endoscopic treatment of UCAN, which suggests the development of sporadic tumours in lesions treated as UCAN. Therefore, we aimed to evaluate differences of immunohistochemistry (IHC) in features and clinicopathological characteristics of intramucosal lesions in patients with ulcerative colitis (UC). METHODS AND RESULTS: We examined 35 intramucosal lesions resected for carcinoma or dysplasia by total colectomy from patients with UC and 71 sporadic adenomas (SAs) endoscopically resected from patients without UC. UC lesions were divided into the conventional UCAN group, defined as p53 mutant pattern and normal expression of ß-catenin, and the non-conventional UCAN group, defined as the rest. Ki-67 distribution, α-methylacyl-CoA racemase (AMACR) expression and mucin phenotypes were compared using IHC, and clinicopathological characteristics were investigated. Conventional and non-conventional UCAN lesions were located in the left colon and rectum. Relative to the SA lesions, UCAN lesions occurred in much younger patients and exhibited more frequent basal distribution of Ki-67 in tumour crypts. Conventional UCAN lesions tended to be non-polyploid and exhibited a higher frequency of normal AMACR expression than SA lesions. UC lesions were heterogeneous-only two of the eight patients with multiple lesions had lesions (both non-conventional UCAN lesions) exhibiting concordant IHC staining features. CONCLUSIONS: The basal pattern of Ki-67 distribution, normal expression of AMACR and a non-intestinal mucin phenotype were determined as characteristic features suggestive of UCAN. Non-polypoid growth was another a key feature of UCAN.

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.

Pregnancy and lactation-associated osteoporosis as a major type of premenopausal osteoporosis: a retrospective cohort study based on real-world data.

BACKGROUND: Pregnancy and lactation-associated osteoporosis (PLO), as well as premenopausal osteoporosis, might be a predictor of future fracture. This study aimed to describe the clinical features of PLO as a subtype of premenopausal osteoporosis and to evaluate medical interventions for it. METHODS: From an administrative claims database including 4,224,246 people in Japan, we classified women for whom the date of childbirth had been defined and who had suffered low-trauma fracture between the ages of 18-47 years as the premenopausal osteoporosis group. A fracture site for which the odds ratio for fractures occurring between 5 months before and 12 months after childbirth (around childbirth) was greater than 1 was considered the PLO site. We classified patients with a fracture at the PLO site around childbirth as the PLO group. The control group consisted of 500 women without fragility fractures. We investigated some drugs and diseases to explore fracture-causing factors, as well as medical interventions such as osteoporosis diagnosis, bone densitometry, anti-osteoporosis pharmacotherapy, and lactation inhibitors. RESULTS: In total, 231 parous women were classified into the premenopausal osteoporosis group. The most common fracture was vertebral fracture and was likely to occur around childbirth, followed by distal radius and sacral fractures, which were rare around childbirth. Considering vertebral, pelvic, and proximal femoral fractures as PLO sites, 56 women with 57 PLO fractures were classified into the PLO group. The incidence of PLO was estimated at 460 per million deliveries. Ovulation disorder and high maternal age were associated with the development of PLO. Vertebral fracture was the most common PLO fracture. It was mainly diagnosed a few months, and possibly up to 1 year, postpartum. PLO patients with vertebral fractures underwent more medical interventions than did those with other fractures, but they were still inadequate. CONCLUSIONS: PLO with vertebral fracture was one of the major types of premenopausal osteoporosis. The prevalence of PLO is considered to be higher than previously thought, indicating the presence of potentially overlooked patients. More timely interventions for PLO might lead to the improved management of latent patients with premenopausal osteoporosis and reduce future fracture risk.

Feasibility of an animal model for long-term mechanical circulatory support with Impella 5.5 implanted through carotid artery access in sheep.

Impella is a mechanical circulatory support device of a catheter-based intravascular microaxial pump for left ventricular support and unloading. However, nonclinical studies assessing the effects of the extended duration of left ventricular unloading on cardiac recovery are lacking. An animal model using Impella implanted with a less invasive procedure to enable long-term support is required. This study aimed to evaluate the feasibility of an animal model for long-term support with Impella 5.5 implanted through carotid artery access in sheep.Impella 5.5 was implanted in four sheep through the proximal region of the left carotid artery without a thoracotomy, and myocardial injuries were induced by coronary microembolization. Support by Impella 5.5 was maintained for 4 weeks, and the animals were observed. The position of Impella 5.5 and cardiac function was evaluated using cardiac computer tomography at 2 and 4 weeks after implantation.All four animals completed the 4-week study without major complications. The discrepancy in the Impella 5.5 flow rate between the conscious and anesthetized states was observed depending on the device's position. Animals in whom the inflow was above the left ventricular papillary muscle had a relatively high flow rate under the maximum performance level without a suction alarm during the conscious state. Pathological changes in the aortic valve were observed. Cardiac function under the minimum performance level was observed with no remarkable deterioration.The animal model with myocardial injuries supported for 4 weeks by Impella 5.5 implanted through carotid artery access in sheep was feasible.

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.

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.

Comparison of fixed and flexible progestin-primed ovarian stimulation in women classified in patient-oriented strategies encompassing individualized oocyte number (POSEIDON) group 4.

PURPOSE: This study aimed to compare the fixed and flexible protocols for progestin-primed ovarian stimulation (PPOS) in poor ovarian responders. METHODS: This retrospective study included 95 poor ovarian responders classified using the Patient-Oriented Strategies Encompassing Individualized Oocyte Number group 4 criteria. Treatment involved assisted reproductive medicine using fixed and flexible PPOS protocols at Shiga University of Medical Science between July 2019 and August 2023. PPOS cycles were assigned to the fixed and flexible groups at the discretion of attending physicians. The results of assisted reproductive medicine were compared between groups. RESULTS: The fixed and flexible groups included 68 and 27 patients, respectively. The flexible group obtained more retrieved oocytes and two pro-nuclei than the fixed group, without an early luteinizing hormone surge. Multiple linear regression analysis demonstrated that differences in protocols and anti-müllerian hormone (AMH) levels were related to the number of retrieved oocytes. The differences in protocols were more strongly correlated with the number of oocytes than with the AMH levels. CONCLUSION: Among poor ovarian responders, the flexible PPOS protocol provided more retrieved oocytes than the fixed PPOS protocol, possibly because the total dosage of progestins was lower in the flexible group and progestins were not administered at the time when ovarian stimulation was initiated.

Outcomes of noncurative endoscopic submucosal dissection for T1 colorectal cancer: Prospective, multicenter, cohort study in Japan.

OBJECTIVES: This study investigated the incidence of lymph node metastasis and long-term outcomes in patients with T1 colorectal cancer where endoscopic submucosal dissection (ESD) resulted in noncurative treatment. It is focused on those with deep submucosal invasion, a factor considered a weak predictor of lymph node metastasis in the absence of other risk factors. METHODS: This nationwide, multicenter, prospective study conducted a post-hoc analysis of 141 patients with T1 colorectal cancer ≥20 mm where ESD of the lesion resulted in noncurative outcomes, characterized by poor differentiation, deep submucosal invasion (≥1000 µm), lymphovascular invasion, high-grade tumor budding, or positive vertical margins. Clinicopathologic features and patient prognoses focusing on lesion sites and additional surgery requirements were evaluated. Lymph node metastasis incidence in the low-risk T1 group, identified by deep submucosal invasion as the sole high-risk histological feature, was assessed. RESULTS: Lymph node metastasis occurred in 14% of patients undergoing additional surgery post-noncurative endoscopic submucosal dissection for T1 colorectal cancer. In the low-risk T1 group, in the absence of other risk factors, the frequency was 9.7%. The lymph node metastasis rates in patients with T1 colon and rectal cancers did not differ significantly (14% vs. 16%). Distant recurrence was observed in one patient (2.3%) in the ESD only group and in one (1.0%) in the additional surgery group, both of whom had had rectal cancer removed. CONCLUSION: The risk of lymph node metastasis or distant occurrence was not negligible, even in the low-risk T1 group. The findings suggest the need for considering additional surgery, particularly for rectal lesions (Clinical Trial Registration: UMIN000010136).

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.

[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.

[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.

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.

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.

Comparing hoof dimensional measurements in cows based on 3D image creation and manual measurement.

In this study, the accuracy of using 3D measurements from a 3D image creation application (3DICA) as a potential tool for measuring hoof dimensions in cattle was determined. Fifty distal limbs of cattle obtained from a slaughterhouse were included after the data was trimmed by the functional hoof trimming method. The lengths of six dimensional variables determined by manual measurements served as the true values. Then, the images of these hooves were captured with the 3DICA, and the same variables were determined by the measurement function in the 3DICA. A strong positive correlation was obtained between the 3D and manual measurements for five of the six points, and the mean difference was within 2 mm at all six points. However, the limits of agreement varied at three of the six points. In conclusion, compared with manual measurements, the 3D measurements provided approximately equivalent measurements for the hoof dimensions. However, these findings are preliminary, and further investigations are needed.

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.

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.

Characteristics of Epithelioid Trophoblastic Tumor: Endoscopic and Magnetic Resonance Imaging Findings.

Introduction: Epithelioid endothelial tumor (ETT) is an extremely rare tumor that typically occurs in women of reproductive age. The diagnosis tends to be delayed because it often necessitates a total hysterectomy. Therefore, it is important to understand ETT macroscopic and imaging findings. Here, we report a case of ETT with detailed macroscopic and imaging findings. Case Presentation: A 39-year-old woman with positive pregnancy test results was admitted to a nearby hospital. No gestational sac was found in the uterus, and magnetic resonance imaging (MRI) revealed a cystic mass of approximately 7 cm that extended continuously from the anterior wall of the lower uterine segment into the pelvic cavity. She underwent laparoscopic and hysteroscopic surgeries for a ruptured cervical pregnancy. Pathology of the specimens obtained from this surgery did not allow for the diagnosis of ETT. Two months after the surgery, as the serum human chorionic gonadotropin ß subunit (ß-HCG) level did not decrease, she was diagnosed with low-grade gestational trophoblastic neoplasia, leading to the administration of chemotherapy. After three regimens of chemotherapy over 9 months, her ß-HCG level decreased but did not reach normal levels. Ultimately, a total hysterectomy was performed. The pathological diagnosis was mixed ETT and choriocarcinoma. A literature review revealed several cases similar to ours. Conclusion: ETT in the lower uterus often perforates the myometrium and forms cystic lesions in the retroperitoneal space or subserosa. The MRI and laparoscopic/hysteroscopic findings in this case may have contributed to the early diagnosis of ETT.