Duodenal stenosis due to small lymphocele after para-aortic lymphadenectomy: A case report and review of the literature.

OBJECTIVE: We present an unusual case of a small para-aortic lymphocele causing duodenal stenosis after lymphadenectomy and discuss its treatment. CASE REPORT: Our case involved a 57-year-old woman with endometrial cancer who underwent surgery, including para-aortic lymphadenectomy. On postoperative day 7, projectile vomiting occurred. Computed tomography (CT) revealed a small lymphocele in the dorsal duodenum, causing duodenal stenosis. Transpercutaneous and transduodenal puncture or surgical procedures were difficult because the cyst was too small. Per endoscopic and gastrointestinal series findings on the postoperative day 22, a liquid diet was presumed to be able to pass through the narrow portion. Hence, concentrated liquid food was administered orally; no vomiting occurred. At 2 months postoperatively, CT showed no lymphocele. CONCLUSION: Conservative treatment involving waiting for spontaneous lymphocele reduction with a concentrated fluid diet may be considered in such cases if fluid passage is confirmed with endoscopy and gastrointestinal series.

A New Self-Expandable Metallic Stent with Low Axial Force and a High Axial Force Zero-Border Shows a Very Low Perforation Rate in Malignant Colorectal Obstruction: A Japanese Multicenter Prospective Study.

Background: Recently, there has been a significant increase in the utilization of self-expandable metallic stents (SEMSs) for treating malignant colorectal obstructions through colorectal stenting. The mechanical properties of SEMSs are usually considered to affect clinical outcomes of patients with malignant colorectal obstructions. Methods: This single-arm, prospective, multicenter study of SEMS with a lower axial force and high axial force zero-border included 200 patients with malignant colorectal obstruction. Technical and clinical success, stent patency, and adverse events associated with SEMS placement were evaluated. Results: One patient was excluded, and 199 patients were evaluated. The treatment intent was bridge-to-surgery in 129 and palliation in 70 patients. Technical and clinical success rates were 99.5% and 97.0%, respectively. The percentage of the ColoRectal Obstruction Scoring System scores of 3 or higher improved significantly from 19.2% before placement to 93.9% after placement. Clinical success was not achieved in five patients due to insufficient stent expansion in four patients and stent occlusion in one patient. Only one patient underwent emergency surgery for perforation of the proximal colon, far from where the stent was placed; the rescue procedure was not performed, despite no improvement in proximal dilatation due to insufficient stent expansion. Among the palliation cohort, 15 patients received chemotherapy, including molecular-targeted agents such as bevacizumab. There were no fatal cases related to stent placement. Conclusions: For management of malignant colorectal obstruction, this newly developed SEMS with low axial force and a high axial force zero-border showed high technical and clinical success rates, and an extremely low perforation rate (0.5%).

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).

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.

Emergency Surgery for Adnexal Torsion in Late Preterm Pregnancy Causing Term Vaginal Delivery: A Case Report and Literature Review.

Adnexal cyst torsion in late preterm pregnancies is rare, but it frequently causes secondary uterine contractions. Thus, deciding on performing a simultaneous cesarean section due to the potential for early postoperative labor onset is crucial despite no obstetric indications. Here, we report a case of adnexal torsion at 34 weeks of gestation treated with emergency surgery, followed by a full-term vaginal delivery, along with a literature review. A 31-year-old primigravida at 34 weeks and four days of gestation presented to the emergency department with right lower abdominal pain. An emergency laparotomy was performed to achieve term delivery, suspecting right ovarian cyst torsion without signs of fetal distress. General anesthesia with sevoflurane was selected over spinal anesthesia, considering the incision height. The patient was placed in the left lateral decubitus position on the operating table to ensure proper visualization and maintain uterine circulation. A 4-cm transverse skin incision was made under ultrasound guidance, revealing the twisted right paratubal cyst immediately beneath. The cyst was excised, and the torsion was relieved. The postoperative course was uneventful, and spontaneous labor occurred at 39 weeks and six days of gestation, resulting in a vaginal delivery at 40 weeks. This case demonstrates that even late preterm adnexal torsion can be managed safely with appropriate surgical techniques, allowing for a subsequent term vaginal delivery.

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.

Intracellular cartilage oligomeric matrix protein augments breast cancer resistance to chemotherapy.

Chemotherapy persists as the primary intervention for breast cancer, with chemoresistance posing the principal obstacle to successful treatment. Herein, we show that cartilage oligomeric matrix protein (COMP) expression leads to increased cancer cell survival and attenuated apoptosis under treatment with several chemotherapeutic drugs, anti-HER2 targeted treatment, and endocrine therapy in several breast cancer cell lines tested. The COMP-induced chemoresistance was independent of the breast cancer subtype. Extracellularly delivered recombinant COMP failed to rescue cells from apoptosis while endoplasmic reticulum (ER)-restricted COMP-KDEL conferred resistance to apoptosis, consistent with the localization of COMP in the ER, where it interacted with calpain. Calpain activation was reduced in COMP-expressing cells and maintained at a lower level of activation during treatment with epirubicin. Moreover, the downstream caspases of calpain, caspases -9, -7, and -3, exhibited significantly reduced activation in COMP-expressing cells under chemotherapy treatment. Chemotherapy, when combined with calpain activators, rendered the cells expressing COMP more chemosensitive. Also, the anti-apoptotic proteins phospho-Bcl2 and survivin were increased in COMP-expressing cells upon chemotherapy. Cells expressing a mutant COMP lacking thrombospondin repeats exhibited reduced chemoresistance compared to cells expressing full-length COMP. Evaluation of calcium levels in the ER, cytosol, and mitochondria revealed that COMP expression modulates intracellular calcium homeostasis. Furthermore, patients undergoing chemotherapy or endocrine therapy demonstrated significantly reduced overall survival time when tumors expressed high levels of COMP. This study identifies a novel role of COMP in chemoresistance and calpain inactivation in breast cancer, a discovery with potential implications for anti-cancer therapy.

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.

Usefulness of magnifying endoscopy for diagnosis of sessile serrated lesion with dysplasia or carcinoma: Large retrospective study.

Background and study aims Sessile serrated lesions (SSLs) are precursor lesions in the serrated neoplasia pathway that lead to invasive carcinoma from dysplasia arising from SSLs. This study aimed to elucidate the clinicopathological and endoscopic features of SSLs with and without dysplasia or carcinoma. Patients and methods We reviewed the clinicopathological and endoscopic data from all colorectal lesions pathologically diagnosed as SSLs at Juntendo University Hospital, Tokyo, Japan, between 2011 and 2022. In addition to conventional endoscopic findings, we retrospectively evaluated magnifying endoscopic findings with narrow-band imaging (NBI) or blue laser imaging (BLI) using the Japan NBI Expert Team system and analyzed pit patterns using magnified chromoendoscopic images. Results Of the 2,132 SSLs, 92.5%, 4.7%, 1.8%, and 0.9% had no dysplasia, low-grade dysplasia, high-grade dysplasia, and submucosal invasive carcinoma, respectively. Older age, the proximal colon, and larger lesions were more frequently associated with SSLs with dysplasia or carcinoma. However, 41.3% of the SSLs with dysplasia or carcinoma were ≤ 10 mm in size. Endoscopic findings, such as (semi)pedunculated morphology, double elevation, central depression, and reddishness, were frequently found in SSLs with dysplasia or carcinoma. Furthermore, magnifying endoscopy using NBI or BLI and magnifying chromoendoscopy showed high sensitivity, specificity, and accuracy for diagnosing dysplasia or carcinoma within SSLs. Conclusions SSLs with and without dysplasia or carcinoma exhibit distinct clinicopathological and endoscopic features. In an SSL series, conventional endoscopic characteristics in addition to use of magnifying endoscopy may be useful for accurately diagnosing advanced histology within an SSL.

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.

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.

Evaluating the impact of application of anaerobic bacterial fermentation enhancer on digital dermatitis.

The control of digital dermatitis (DD) among cattle is crucial; however, effective and environmentally-sound control measures have yet to be identified. From the monitoring data of DD which were recorded during regular hoof trimmings in a farm in Hokkaido, Japan, we detected a decrease in the DD prevalence in a herd where an anaerobic bacterial fermentation enhancer (ABFE) was distributed. The possible effect of ABFE was analyzed using a retrospective repeated cross-sectional design. The prevalence of DD decreased over time in the ABFE-distributed group. Furthermore, a selected regression model indicated the time-dependent enhancement of the decreasing trend. While potential coincidental factors may influence, this study provides a basis for further research on the preventive effect of ABFE against DD.

Novel physiological analysis using blood flow velocity for colonic polyps: Pilot study.

Real-time visualization of red blood cell flow inside subepithelial microvessels is performed with magnifying endoscopy. However, microvascular blood flow velocity in the colorectum has not been investigated. Here, we aimed to evaluate the blood flow velocity of microvessels of colonic polyps and to compare it with that of surrounding mucosa. We examined 50 lesions, including 30 adenomas (ADs) and 20 hyperplastic polyps (HPs). Blood flow velocities of lesions and their surrounding mucosa were evaluated using magnifying blue laser imaging (BLI) prior to endoscopic resection. Calculation of mean blood flow velocities was based on mean movement distance of one tagged red blood cell using split video images of magnifying BLI. Mean microvascular blood flow velocity was significantly lower in ADs (1.65±0.66 mm/sec; range 0.46-2.90) than in HPs (2.83±1.10 mm/sec; 1.07-4.50) or the surrounding mucosa (3.73±1.11 mm/sec; 1.80-6.20; P <0.001). The blood flow velocity rate compared with the surrounding mucosa was significantly lower in ADs (0.41±0.16; 0.10-0.82) than in HPs (0.89±0.25; 0.46-1.51; P <0.001). We found that mean microvascular blood flow velocity was significantly lower in ADs than in HPs and the surrounding non-neoplastic mucosa. These findings indicate that a novel dynamic approach with microvascular blood flow velocity using magnifying endoscopy may be useful in assessing physiological differences between ADs and HPs.

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.

Residual Recurrence of a Small Intestinal Capillary Hemangioma with Obscure Gastrointestinal Bleeding Treated by Double-Balloon Endoscopy: A Case Report and Literature Review.

An 86-year-old man presented with anemia. He underwent abdominal contrast-enhanced computed tomography, gastroscopy, and colonoscopy without any bleeding detected. Small bowel capsule endoscopy (SBCE) revealed a reddish polypoid lesion with blood oozing into the jejunum. Antegrade double-balloon endoscopy (DBE) revealed a 5 mm sized protrusion into the jejunum. Endoscopic mucosal resection (EMR) was difficult; the lesion was snared and resected before energization. Clips prevented further bleeding and the lesion's position was marked with a tattoo. Histopathological examination of the lesion led to a diagnosis of capillary hemangioma. After 11 months, the patient was again anemic. A reddish polypoid lesion oozing blood near the tattoo was found by SBCE. Another antegrade DBE showed a 7 mm sized protrusion near the tattoo. The lesion was successfully treated by EMR. Histopathological examination revealed the residual recurrence of a small intestinal capillary hemangioma. The patient recovered from anemia after the EMR. Two months later, SBCE showed no findings around the tattoo. Hemangiomas account for 7-10% of benign small intestinal tumors; most are cavernous hemangiomas, and capillary hemangiomas are rare. We report a rare case of a recurring small intestinal capillary hemangioma detected by SBCE and treated using DBE. We also review the literature.

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.

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.

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.