Trends and associations between kinesiophobia and knee function from preoperatively to three and six months postoperatively in patients post-ACL reconstruction surgery.

OBJECTIVE: This study aimed to clarify the relationship between the transition of kinesiophobia and knee joint function from the preoperative period to three months postoperative, the time to resume running, six months post-ACLR, and the goal time to resume sports. METHODS: 54 patients who underwent initial ACLR were included in this study. The Tampa Scale for Kinesiophobia-11 (TSK-11) was used to assess kinesiophobia. One-way ANOVA was performed for the preoperative, three-month postoperative, and six-month postoperative endpoints. To examine changes in knee function associated with changes in TSK-11, we calculated correlations between the differences at each time point. RESULTS: TSK-11 decreased significantly at both three and six months postoperatively compared with the preoperative level, but there was no significant change between three months and six months postoperatively. Similar to the decrease in TSK-11 from preoperatively to three and six months postoperatively, there was an improvement in flexion ROM, Pain, Subjective knee function, but none of these changed significantly from three to six months postoperatively. CONCLUSION: There may be significant improvements in knee function associated with TSK-11 reduction up to three months postoperatively.

A comparison of reoperation rates after single-level anterior cervical discectomy and fusion (ACDF) between the procedures with and without anterior plate fixation.

INTRODUCTION: The plate fixation for anterior cervical discectomy and fusion (ACDF) has become increasingly widespread for facilitating early mobilization and improving fusion rate. However, apart from multilevel operations, there is still some controversy over its use for single-level ACDF. This retrospective study has compared the reoperation rates after single-level ACDFs performed at our institution between the procedures with and without plate fixation. METHODS: This retrospective study included a total of 131 patients with???1-year of follow-up after a single-level ACDF, consisting of 100 patients without plating (conventional ACDF) and 31 patients with plate fixation (plated ACDF). RESULTS: Eleven patients (8.4% of all patients):four conventional ACDFs (4% of the conventional ACDFs) and seven plated ACDFs (22.6% of the plated ACDFs), had reoperation surgeries. The incidence of reoperation was significantly higher in the plated ACDFs than in the conventional ACDFs (P=0.0037). The log-rank test revealed a significant difference (P=0.00003) in 5-year reoperation-free survival rates between the conventional (96.9%) and the plated groups (68.3%). CONCLUSION: Anterior cervical plating may have a negative impact on the adjacent segment integrity, resulting in an increased reoperation rate after a single-level ACDF at relatively shorter postoperative time points. J. Med. Invest. 70 : 334-342, August, 2023.

THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer.

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.

Pancreatic metastasis from lung adenocarcinoma.

TTF-1 is a highly useful marker to assist in differentiating between pulmonary and nonpulmonary, nonthyroid adenocarcinomas. Our case shows that TTF-1 is highly useful in differentiating between pancreatic metastasis from lung adenocarcinoma and primary pancreatic cancer, especially when the clinical course and imaging findings are not helpful for differentiating them.

Computer-aided demarcation of early gastric cancer: a pilot comparative study with endoscopists.

BACKGROUND: Precise area diagnosis of early gastric cancer (EGC) is critical for reliable endoscopic resection. Computer-aided diagnosis (CAD) shows strong potential for detecting EGC and reducing cancer-care disparities caused by differences in endoscopists' skills. To be used in clinical practice, CAD should enable both the detection and the demarcation of lesions. This study proposes a scheme for the detection and delineation of EGC under white-light endoscopy and validates its performance using 1-year consecutive cases. METHODS: Only 300 endoscopic images randomly selected from 68 consecutive cases were used for training a convolutional neural network. All cases were treated with endoscopic submucosal dissection, enabling the accumulation of a training dataset in which the extent of lesions was precisely determined. For validation, 462 cancer images and 396 normal images from 137 consecutive cases were used. From the validation results, 38 randomly selected images were compared with those delineated by six endoscopists. RESULTS: Successful detections of EGC in 387 cancer images (83.8%) and the absence of lesions in 307 normal images (77.5%) were achieved. Positive and negative predictive values were 81.3% and 80.4%, respectively. Successful detection was achieved in 130 cases (94.9%). We achieved precise demarcation of EGC with a mean intersection over union of 66.5%, showing the extent of lesions with a smooth boundary; the results were comparable to those achieved by specialists. CONCLUSIONS: Our scheme, validated using 1-year consecutive cases, shows potential for demarcating EGC. Its performance matched that of specialists; it might therefore be suitable for clinical use in the future.

The area of residual tumor predicts esophageal squamous cell carcinoma prognosis following neoadjuvant chemotherapy.

PURPOSE: To clarify the utility of the area of residual tumor for patients with esophageal squamous cell cancer treated with neoadjuvant chemotherapy. METHODS: We enrolled 186 patients with esophageal squamous cell cancer who underwent surgical resection following neoadjuvant chemotherapy at our hospital. Using digital images, we measured the area of residual tumor at the maximum plane of the specimen and divided the patient into three groups as follows: 0 (area = 0 mm2), low (area = 0-40 mm2), and high (area ≥ 40 mm2). The clinicopathological factors and prognosis were compared among these groups. RESULTS: The median area of the residual tumor was 15.0 mm2　(range 0-1,448.8 mm2). Compared with the 0 and low group, the high group was significantly associated with poorer recurrence-free survival (all P < .001) and overall survival (P < .001 [vs. 0] and P = .017 [vs low]). The area of residual tumor, ypN, tumor regression grade, and lymphovascular invasion were independent predictors of recurrence-free survival. By dividing the patients using a combination of the area of residual tumor and lymphovascular invasion, the high and/or lymphovascular invasion ( +) group displayed significantly poor recurrence-free survival than the 0 group and low/lymphovascular invasion ( -) group. However, there was no significant difference in the recurrence-free survival between the 0 group and low/lymphovascular invasion ( -) group. CONCLUSION: The area of residual tumor is a promising histopathological prognostic factor for patients with esophageal squamous cell cancer treated with neoadjuvant chemotherapy. Moreover, it is a possible candidate histopathological factor for postoperative chemotherapy selection.

Modeling Low Muscle Mass Screening in Hemodialysis Patients.

INTRODUCTION: Computed tomography (CT) can accurately measure muscle mass, which is necessary for diagnosing sarcopenia, even in dialysis patients. However, CT-based screening for such patients is challenging, especially considering the availability of equipment within dialysis facilities. We therefore aimed to develop a bedside prediction model for low muscle mass, defined by the psoas muscle mass index (PMI) from CT measurement. METHODS: Hemodialysis patients (n = 619) who had undergone abdominal CT screening were divided into the development (n = 441) and validation (n = 178) groups. PMI was manually measured using abdominal CT images to diagnose low muscle mass by two independent investigators. The development group's data were used to create a logistic regression model using 42 items extracted from clinical information as predictive variables; variables were selected using the stepwise method. External validity was examined using the validation group's data, and the area under the curve (AUC), sensitivity, and specificity were calculated. RESULTS: Of all subjects, 226 (37%) were diagnosed with low muscle mass using PMI. A predictive model for low muscle mass was calculated using ten variables: each grip strength, sex, height, dry weight, primary cause of end-stage renal disease, diastolic blood pressure at start of session, pre-dialysis potassium and albumin level, and dialysis water removal in a session. The development group's adjusted AUC, sensitivity, and specificity were 0.81, 60%, and 87%, respectively. The validation group's adjusted AUC, sensitivity, and specificity were 0.73, 64%, and 82%, respectively. DISCUSSION/CONCLUSION: Our results facilitate skeletal muscle screening in hemodialysis patients, assisting in sarcopenia prophylaxis and intervention decisions.

Prospective study on the risk of transmission due to droplets and aerosols during an endoscopic procedure and the usefulness of extraoral suction devices.

OBJECTIVES: Endoscopy poses a high risk of severe acute respiratory syndrome coronavirus 2 infection for medical personnel due to the dispersal of aerosols from the patient. We investigated the location and size of droplets generated during esophagogastroduodenoscopy (EGD) and endoscopic submucosal dissection (ESD), the contamination of the surrounding area before and after the procedures, and the effectiveness of using an extraoral suction device (Free arm arteo; TOKYO GIKEN, Inc., Tokyo, Japan). METHODS: Patients who consented to the study and underwent EGD or ESD between December 8, 2020, and April 15, 2021, at the National Cancer Center East Hospital were included. Adenosine triphosphate (ATP) hygiene monitoring tests and a particle counter were used for measurements. RESULTS: Assessments were performed on 22 EGD and 15 ESD cases. ATP hygiene monitoring tests showed significant elevations at three sites near the patient, and two sites 1.5 m away, for EGD, and at four sites near the patient and 1.5 m away for ESD. In both ESD and EGD, extraoral suction devices reduced the extent of the contamination. Particles <5 µm in size were generated during endoscopic procedures and dispersed from both the forceps hole and the patient's mouth. The extraoral suction device did not reduce the number of particles generated. CONCLUSIONS: During endoscopic procedures, cleaning the surrounding environment is important in addition to standard precautions the endoscopist and caregivers take. The use of extraoral suction devices can also potentially reduce contamination of the surrounding environment.

A case of neuroendocrine neoplasm of the minor duodenal papilla.

A 61-year-old woman was referred to our hospital for intraductal papillary mucinous neoplasm with no symptoms. Magnetic resonance imaging (MRI) depicted a 15 mm nodular lesion at the descending portion of duodenum. Upper gastrointestinal endoscopy showed a submucosal tumor-like mass at the minor duodenal papilla. A boring biopsy of the tumor revealed a neuroendocrine neoplasm (NEN). Various blood hormone tests were all within normal limits, and the tumor was considered to be nonfunctional. Contrast-enhanced computed tomography showed no obvious distant metastasis, and subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) was performed. Histopathological examination revealed a dense cluster of spindle-shaped cells forming a sheet-like foci and areas showing glandular lumen formation, and immunohistochemistry showed synaptophysin ( + ), chromogranin ( + ). Mitotic rate was about 11 mitoses per 2 square millimeters, Ki-67 index was about 0.2%. She was pathologically diagnosed with NEN G2 at the minor duodenal papilla with regional lymph node metastasis according to the WHO2010 classification. The patient has been currently under outpatient observation with a good postoperative course. Review of the literature identified 43 cases of NENs of the minor duodenal papilla. NENs of the minor duodenal papilla have a high rate of lymph node metastasis, even if the tumor size is small.

A case of pancreas divisum with marked dilatation of dorsal pancreatic duct.

A 56-year-old man was referred to our hospital for fever and back pain. Contrast-enhanced computed tomography, magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound revealed marked dilatation of the main pancreatic duct from head to tail and surrounding cysts with no evidence of pancreatic masses or obstructive causes. Endoscopic retrograde pancreatography (ERP) from the major duodenal papilla showed a short and narrow ventral pancreatic duct and ERP from the minor duodenal papilla revealed a dilated dorsal pancreatic duct with a narrow branch which connected to the ventral pancreatic duct. Intra-ductal ultrasound showed no nodules in the main pancreatic duct, and pancreatic cytology was negative. Peroral pancreatoscopy showed that the main pancreatic duct was covered with normal epithelium without tumors. Biopsy from the pancreatic duct showed no neoplastic changes. He was diagnosed with incomplete pancreas divisum accompanied by dilatation of dorsal pancreatic duct. Sphincterotomy of the minor duodenal papilla was performed. Seven months later, MRCP re-examination showed that the main pancreatic duct dilatation was relieved. Review of the literature identified 10 cases of pancreas divisum accompanied by dilatation of main pancreatic duct to date. To our knowledge, this is the first reported case of pancreas divisum with pancreatic duct dilatation without Santorinicele.

A Novel Rat Model to Study Postsurgical Pain After Joint Replacement Surgery.

Purpose: The mechanisms underlying chronic postsurgical pain after joint replacement (JR) are complex, and it has been suggested that chronic postsurgical pain can develop as a result of inadequate acute pain management. Few studies have addressed acute pain after JR using specific animal models. This study aimed to develop a novel JR model focused on postsurgical pain assessment and the time course of pain recovery. Materials and Methods: Rats were allocated to the following three groups: sham (joint exposure), joint destruction (JD; resection of the femoral head), and JR (femoral head replacement using an originally developed implant). The time course of postsurgical pain behavior was measured using a dynamic weight-bearing apparatus, along with radiological assessments. The expression of calcitonin gene-related peptide-immunoreactive (CGRP-IR) neurons in the dorsal root ganglion (DRG) was evaluated by immunohistochemistry on days 28 and 42. Results: The ratio of weight-bearing distribution in the JR group gradually recovered from day 14 and reached the same level as that in the sham group on day 42, which was significantly greater than that in the JD group after day 7 (p<0.05). Radiologically, no significant issues were found, except for transient central migration of the implant in the JR group. The percentage of CGRP-IR DRG neurons in the JR group was significantly lower than that in the JD group on day 28 (mean, 37.4 vs 58.1%, p<0.05) and day 42 (mean, 32.3 vs 50.0%, p<0.05). Conclusion: Our novel JR model presented acute postsurgical pain behavior that was successfully recovered to the baseline level at day 42 after surgery. Difference of the pain manifestation between the JR and JD groups could be supported by the expression of CGRP-IR in DRG neurons. This model is the first step toward understanding detailed mechanisms of post-JR pain.

The usefulness of a double-balloon endolumenal interventional platform for colorectal endoscopic submucosal dissection by non-expert endoscopists in a porcine model (with video).

BACKGROUND: Endoscopic submucosal dissection (ESD) is an optimal treatment for colorectal tumors; however, it is technically difficult, especially for non-experts. Therefore, a device that helps non-experts perform colorectal ESD would be beneficial. A double-balloon endolumenal interventional platform (DEIP) was recently developed to assist colorectal ESD through endoscope stabilization and traction. This study assessed the usefulness of colorectal ESD using the DEIP (DEIP-ESD) by endoscopists, including non-experts, in a living porcine model. METHODS: Two pigs were used to perform eight DEIP-ESD and eight conventional cap-assisted ESD (C-ESD) procedures. Three experts and five non-experts each resected one lesion using DEIP-ESD and one using C-ESD. We evaluated the treatment outcomes and performed stratified analyses between the experts and non-experts. RESULTS: Dissection speed was significantly faster in DEIP-ESD than in C-ESD (13.3 mm2/min vs 28.5 mm2/min, P = 0.002). However, the total procedure time did not differ significantly between DEIP-ESD and C-ESD. In the stratified analyses, the dissection speed of non-experts was significantly faster in DEIP-ESD than in C-ESD (10.9 mm2/min vs 25.1 mm2/min, P = 0.016), while that of experts increased in DEIP-ESD but to a lesser extent (19.1 mm2/min vs 28.8 mm2/min, P = 0.1). The total procedure time did not differ between DEIP-ESD and C-ESD for both experts and non-experts. The self-completion rate of non-experts also increased in DEIP-ESD. Moreover, the number of muscularis propria injuries induced by non-experts was fewer in DEIP-ESD than in C-ESD. CONCLUSIONS: DEIP could facilitate colorectal ESD by improving dissection efficiency without increasing adverse events, especially when performed by non-experts.

Finger trembling improvement after surgery in Hirayama disease: a case report.

INTRODUCTION: Finger trembling is a characteristic physical finding in Hirayama disease. Although conservative treatment is recommended to stop disease progression, surgery is optional in some cases. However, the postoperative recovery of finger trembling is scarcely reported. CASE PRESENTATION: A 26-year-old Japanese female patient whose chief complaint was left finger trembling with active finger extension presented at our hospital. Hand weakness without muscle atrophy of the left arm was observed. MRI showed left-side oriented intramedullary signal change with concomitant cord atrophy at C4-5 and C5-6. The CT myelogram (CTM) on flexion showed anterior cord compression and anterior shift of posterior dura matter from C4 to C6. And CTM on extension showed the resolution of both findings. Electrophysiological studies showed active and chronic neuronal damage and preserved motor neuron pool of hand muscle. Since she had exhibited a gradual aggravation of symptoms over a period of 5 years, she underwent anterior cervical discectomy and fusion after careful assessment of both conservative and surgical treatment. Finger trembling recovered soon after surgery. DISCUSSION: Finger trembling is an unfamiliar physical finding in terms of postoperative recovery prediction. Anterior horn cell impairment is postulated as a cause of finger trembling. Postural restoration of spinal cord shape and cerebrospinal fluid around the cord with preserved neural function could facilitate functional recovery.

The characteristics of missed pharyngeal and laryngeal cancers at gastrointestinal endoscopy.

OBJECTIVES: Understanding the miss rate and characteristics of missed pharyngeal and laryngeal cancers during upper gastrointestinal endoscopy may aid in reducing the endoscopic miss rate of this cancer type. However, little is known regarding the miss rate and characteristics of such cancers. Therefore, the aim of this study was to investigate the upper gastrointestinal endoscopic miss rate of oro-hypopharyngeal and laryngeal cancers, the characteristics of the missed cancers, and risk factors associated with the missed cancers. METHODS: Patients who underwent upper gastrointestinal endoscopy and were pathologically diagnosed with oro-hypopharyngeal and laryngeal squamous cell carcinoma from January 2019 to November 2020 at our institution were retrospectively evaluated. Missed cancers were defined as those diagnosed within 15 months after a negative upper gastrointestinal endoscopy. RESULTS: A total of 240 lesions were finally included. Eighty-five lesions were classified as missed cancers, and 155 lesions as non-missed cancers. The upper gastrointestinal endoscopic miss rate for oro-hypopharyngeal and laryngeal cancers was 35.4%. Multivariate analysis revealed that a tumor size of <13 mm (odds ratio: 1.96, P=0.026), tumors located on the anterior surface of the epiglottis/valleculae (odds ratio: 2.98, P=0.045) and inside of the pyriform sinus (odds ratio: 2.28, P=0.046) were associated with missed cancers. CONCLUSIONS: This study revealed a high miss rate of oro-hypopharyngeal and laryngeal cancers during endoscopic observations. High-quality upper gastrointestinal endoscopic observation and awareness of missed cancer may help reduce this rate.

Serum soluble (pro)renin receptor level as a prognostic factor in patients undergoing maintenance hemodialysis.

The (pro)renin receptor [(P)RR)] is a multifunctional protein that is cleaved to generate the soluble (P)RR [s(P)RR], reflecting the status of the tissue renin-angiotensin system and/or activity of the (P)RR. The serum s(P)RR level is associated with arteriosclerosis, independent of other risk factors, in patients undergoing hemodialysis (HD). This study was conducted to investigate whether the s(P)RR level was associated with new-onset cardiovascular events or malignant diseases and poor prognosis in patients undergoing HD. Overall, 258 patients [70 (61-76) years, 146 males] undergoing maintenance HD were prospectively followed up for 60 months. We investigated the relationships between s(P)RR levels and new-onset cardiovascular events/ malignant diseases and mortality during the follow-up period using Cox proportional hazard analyses. The cumulative incidence of new-onset cardiovascular events (P = 0.009) and deaths (P < 0.001), but not of malignant diseases, was significantly greater in patients with higher serum s(P)RR level (≥ 29.8 ng/ml) than in those with lower s(P)RR level (< 29.8 ng/ml). A high serum s(P)RR level was independently correlated with cardiovascular mortality (95% CI 1.001-1.083, P = 0.046). The serum s(P)RR level was associated with cardiovascular events and mortality, thus qualifying as a biomarker for identifying patients requiring intensive care.

Trophectoderm biopsy for preimplantation genetic test and technical tips: A review.

BACKGROUND: Recently, the Japan Society of Obstetrics and Gynecology initiated a clinical study of preimplantation genetic test for aneuploidy. There will be a great need for a standardized embryo biopsy technique in Japan. However, the gold standard trophectoderm (TE) biopsy procedure has not been established, and this review outlines the clinical use of TE biopsy. METHODS: Based on literature, the method and associated techniques for TE biopsy, a dissection method of TE cells from blastocysts, were investigated. MAIN FINDINGS: Two TE biopsy methods are used, namely assisted hatching (herniating) and non-assisted hatching (direct suction); however, it is not clear which of these methods is superior. It is critical to understand whether the flicking or pulling method is beneficial. CONCLUSION: Non-assisted hatching biopsy method may cause blastocyst collapse with a higher probability, and it may extend the biopsy time. The biopsy procedure should be performed within 3 minutes, and thus direct TE suction may have greater disadvantages. It is a fact that pulling method of TE dissection with laser pulse is simple; however, excess laser shots may induce a higher frequency of mosaicism. It is important to understand that each technique of TE biopsy has benefits and disadvantages.

Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure.

STUDY QUESTION: Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live birth rate and reduce the miscarriage rate in patients with recurrent pregnancy loss (RPL) caused by an abnormal embryonic karyotype and recurrent implantation failure (RIF)? SUMMARY ANSWER: PGT-A could not improve the live births per patient nor reduce the rate of miscarriage, in both groups. WHAT IS KNOWN ALREADY: PGT-A use has steadily increased worldwide. However, only a few limited studies have shown that it improves the live birth rate in selected populations in that the prognosis has been good. Such studies have excluded patients with RPL and RIF. In addition, several studies have failed to demonstrate any benefit at all. PGT-A was reported to be without advantage in patients with unexplained RPL whose embryonic karyotype had not been analysed. The efficacy of PGT-A should be examined by focusing on patients whose previous products of conception (POC) have been aneuploid, because the frequencies of abnormal and normal embryonic karyotypes have been reported as 40-50% and 5-25% in patients with RPL, respectively. STUDY DESIGN, SIZE, DURATION: A multi-centre, prospective pilot study was conducted from January 2017 to June 2018. A total of 171 patients were recruited for the study: an RPL group, including 41 and 38 patients treated respectively with and without PGT-A, and an RIF group, including 42 and 50 patients treated respectively with and without PGT-A. At least 10 women in each age group (35-36, 37-38, 39-40 or 41-42 years) were selected for PGT-A groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients and controls had received IVF-ET for infertility. Patients in the RPL group had had two or more miscarriages, and at least one case of aneuploidy had been ascertained through prior POC testing. No pregnancies had occurred in the RIF group, even after at least three embryo transfers. Trophectoderm biopsy and array comparative genomic hybridisation (aCGH) were used for PGT-A. The live birth rate of PGT-A and non-PGT-A patients was compared after the development of blastocysts from up to two oocyte retrievals and a single blastocyst transfer. The miscarriage rate and the frequency of euploidy, trisomy and monosomy in the blastocysts were noted. MAIN RESULT AND THE ROLE OF CHANCE: There were no significant differences in the live birth rates per patient given or not given PGT-A: 26.8 versus 21.1% in the RPL group and 35.7 versus 26.0% in the RIF group, respectively. There were also no differences in the miscarriage rates per clinical pregnancies given or not given PGT-A: 14.3 versus 20.0% in the RPL group and 11.8 versus 0% in the RIF group, respectively. However, PGT-A improved the live birth rate per embryo transfer procedure in both the RPL (52.4 vs 21.6%, adjusted OR 3.89; 95% CI 1.16-13.1) and RIF groups (62.5 vs 31.7%, adjusted OR 3.75; 95% CI 1.28-10.95). Additionally, PGT-A was shown to reduce biochemical pregnancy loss per biochemical pregnancy: 12.5 and 45.0%, adjusted OR 0.14; 95% CI 0.02-0.85 in the RPL group and 10.5 and 40.9%, adjusted OR 0.17; 95% CI 0.03-0.92 in the RIF group. There was no difference in the distribution of genetic abnormalities between RPL and RIF patients, although double trisomy tended to be more frequent in RPL patients. LIMITATIONS, REASONS FOR CAUTION: The sample size was too small to find any significant advantage for improving the live birth rate and reducing the clinical miscarriage rate per patient. Further study is necessary. WIDER IMPLICATION OF THE FINDINGS: A large portion of pregnancy losses in the RPL group might be due to aneuploidy, since PGT-A reduced the overall incidence of pregnancy loss in these patients. Although PGT-A did not improve the live birth rate per patient, it did have the advantage of reducing the number of embryo transfers required to achieve a similar number live births compared with those not undergoing PGT-A. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Japan Society of Obstetrics and Gynecology and grants from the Japanese Ministry of Education, Science, and Technology. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Transgenic mice that accept Luciferase- or GFP-expressing syngeneic tumor cells at high efficiencies.

Jellyfish green fluorescent protein (GFP) and firefly luciferase can serve as versatile tracking markers for identification and quantification of transplanted cancer cells in vivo. However, immune reactions against these markers can hamper the formation of syngraft tumors and metastasis that follows. Here, we report two transgenic (Tg) mouse lines that express nonfunctional mutant marker proteins, namely modified firefly luciferase (Luc2) or enhanced GFP (EGFP). These mice, named as Tg-mLuc2 and Tg-mEGFP, turned out to be immunologically tolerant to the respective tracking markers and thus efficiently accepted syngeneic cancer cells expressing the active forms of the markers. We then injected intrarectally the F1 hybrid Tg mice (BALB/c × C57BL/6J) with Colon-26 (C26) colon cancer cells that originated from a BALB/c mouse. Even when C26 cells expressed active Luc2 or EGFP, they formed primary tumors in the Tg mice with only 104 cells per mouse compared with more than 106 cells required in the nontransgenic BALB/c hosts. Furthermore, we detected metastatic foci of C26 cells in the liver and lungs of the Tg mice by tracking the specific reporter activities. These results show the usefulness of the Tg mouse lines as recipients for transplantation experiments with the non-self tracking marker-expressing cells.

Amino-terminal enhancer of split gene AES encodes a tumor and metastasis suppressor of prostate cancer.

A major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples. We then performed overexpression and knockdown of AES in human PCa cell lines LNCaP, DU145 and PC3, and determined the effects on proliferation, invasion and metastasis in culture and in a xenograft model. We also compared the PCa phenotypes of Aes/Pten compound knockout mice with those of Pten simple knockout mice. Expression levels of AES were inversely correlated with clinical stages of human PCa. Exogenous expression of AES suppressed the growth of LNCaP cells, whereas the AES knockdown promoted it. We also found that AES suppressed transcriptional activities of androgen receptor and Notch signaling. Notably, AES overexpression in AR-defective DU145 and PC3 cells reduced invasion and metastasis to lymph nodes and bones without affecting proliferation in culture. Consistently, prostate epithelium-specific inactivation of Aes in Ptenflox/flox mice increased expression of Snail and MMP9, and accelerated growth, invasion and lymph node metastasis of the mouse prostate tumor. These results suggest that AES plays an important role in controlling tumor growth and metastasis of PCa by regulating both AR and Notch signaling pathways.

The restorative effects of adipose-derived mesenchymal stem cells on damaged ovarian function.

The clinical application of human adipose-derived mesenchymal stem cells (MSCs) as treatment for intractable diseases or traumatic tissue damage has attracted attention. To address the ability of reactivating injured ovaries, we prepared a rat model with damaged ovaries by using an anticancer agent, cyclophosphamide (CTX). We then investigated the restorative effects on ovarian function and the safety of adipose-derived MSCs (A-MSCs). MSCs were shown to be capable of inducing angiogenesis and restoring the number of ovarian follicles and corpus lutea in ovaries. No deformities, tumor formation or deaths were observed in F1 and F2 rats, indicating that the local injection of MSCs into the ovary did not have any obvious side effects. In addition, the localization of the Y chromosome was investigated using the fluorescent in situ hybridization method by injecting male A-MSCs into the ovaries; as a result, the Y chromosomes were localized not in the follicles, but in the thecal layers. ELISA revealed that A-MSCs secreted higher levels of vascular endothelial cell growth factor (VEGF), insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) than tail fibroblast cells. Quantitative real-time PCR and immunohistochemistry showed that higher expression levels of VEGF, IGF-1 and HGF were observed in CTX-treated ovaries after A-MSC transplantation. These findings suggest that MSCs may have a role in restoring damaged ovarian function and could be useful for regenerative medicine.