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.

The roles of tight junction protein cingulin in human endometrioid endometrial cancer.

The bicellular tight junction molecule cingulin (CGN) binds to microtubules in centrosomes. Furthermore, CGN contributes to the tricellular tight junction (tTJ) proteins lipolysis-stimulated lipoprotein receptor (LSR) and tricellulin (TRIC). CGN as well as LSR decreased during the malignancy of endometrioid endometrial cancer (EEC). Although tTJ protein LSR is involved in the malignancy of some cancers, including EEC, the role of CGN is unknown. In this study, we investigated the roles of CGN with tTJ proteins in human EEC cells by using the CGN-overexpressing EEC cell line Sawano. In 2D cultures, CGN was colocalized with LSR and TRIC at tTJ or at γ-tubulin-positive centrosomes. In immunoprecipitation with CGN antibodies, CGN directly bound to LSR, TRIC, and ß-tubulin. Knockdown of CGN by the siRNA decreased the epithelial barrier and enhanced cell proliferation, migration and invasion, as well as knockdown of LSR. In the Sawano cells cocultured with normal human endometrial stromal cells, knockdown of CGN decreased expression of LSR and TRIC via MAPK and AMPK pathways. In 2.5D cultures, knockdown of CGN induced the formation of abnormal cysts and increased the permeability of FD-4 to the lumen. In 2D and 2.5D cultures, treatment with ß-estradiol with or without EGF or TGF-ß decreased CGN expression and the epithelial permeability barrier and enhanced cell migration, and pretreatment with EW7197+AG1478, U0126 or an anti-IL-6 antibody prevented this. In conclusion, CGN, with tTJ proteins might suppress the malignancy of human EEC and its complex proteins are sensitive to estrogen and growth factors derived from stromal cells.

Restoration of ARID1A Protein in ARID1A-deficient Clear Cell Carcinoma of the Ovary Attenuates Reactivity to Cytotoxic T Lymphocytes.

BACKGROUND/AIM: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. MATERIALS AND METHODS: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. RESULTS: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. CONCLUSION: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.

Analysis of Treatment Response With Proteins Related to Tumor Immunity in Postoperative Irradiated Cervical Cancer Patients.

BACKGROUND/AIM: This study evaluated the association between programmed cell death-ligand 1 (PD-L1) and prognosis in patients with cervical cancer treated with postoperative radiation and the impact of neoadjuvant chemotherapy (NAC) on this association. PATIENTS AND METHODS: Immunohistochemical analysis was performed on biopsy specimens from 42 patients who did not receive NAC and from paired samples before (biopsies) and after (resected tissues) chemotherapy from 46 patients who received NAC to determine the association of PD-L1 with radiotherapy outcomes. RESULTS: In the non-NAC group, patients with ≥10% PD-L1-expressing tumor cells prior to treatment had better recurrence-free survival (RFS) than those with <10% PD-L1-expressing tumor cells (p=0.001). In the NAC group, RFS was significantly lower (p=0.005) in the group with a ≥5% reduction of PD-L1 expression in tumor cells after chemotherapy than in those with <5% reduction. In multivariate analysis, only PD-L1 expression (non-NAC group) and the change in PD-L1 expression (NAC group) were associated with RFS. CONCLUSION: Low PD-L1 expression in a cervical tumor prior to treatment was identified as a risk factor for a poor outcome after postoperative radiotherapy. Furthermore, NAC induces an immunological shift that reduces PD-L1 levels in tumor cells, thereby negatively impacting treatment outcomes.

Prediction of Mismatch Repair Status in Endometrial Cancer from Histological Slide Images Using Various Deep Learning-Based Algorithms.

The application of deep learning algorithms to predict the molecular profiles of various cancers from digital images of hematoxylin and eosin (H&E)-stained slides has been reported in recent years, mainly for gastric and colon cancers. In this study, we investigated the potential use of H&E-stained endometrial cancer slide images to predict the associated mismatch repair (MMR) status. H&E-stained slide images were collected from 127 cases of the primary lesion of endometrial cancer. After digitization using a Nanozoomer virtual slide scanner (Hamamatsu Photonics), we segmented the scanned images into 5397 tiles of 512 × 512 pixels. The MMR proteins (PMS2, MSH6) were immunohistochemically stained, classified into MMR proficient/deficient, and annotated for each case and tile. We trained several neural networks, including convolutional and attention-based networks, using tiles annotated with the MMR status. Among the tested networks, ResNet50 exhibited the highest area under the receiver operating characteristic curve (AUROC) of 0.91 for predicting the MMR status. The constructed prediction algorithm may be applicable to other molecular profiles and useful for pre-screening before implementing other, more costly genetic profiling tests.

Surgical Outcomes of da Vinci Xi™ and da Vinci SP™ for Early-Stage Endometrial Cancer in Patients Undergoing Hysterectomy.

Objectives: This study aimed to evaluate and compare the feasibility and outcomes of two robotic hysterectomy (da Vinci Xi™ vs. da Vinci SP™) systems without lymph node dissection in patients with early-stage endometrial cancer, and assess the postoperative recurrence rate and overall survival of patients. Methods: A retrospective review of 84 patients who underwent robotic hysterectomy for endometrial cancer (stage 1A) was conducted. Surgical procedures, patient characteristics, intraoperative measures, and postoperative outcomes were statistically analyzed. A single gynecologist performed all surgeries. Results: Patient characteristics, average age, and body mass index showed no significant differences between the two models. The total operative time was significantly shorter with da Vinci SP™. Recurrence was identified in only one patient operated on with da Vinci Xi™. All patients were alive during analysis, with a median overall survival of 38 and 9 months for da Vinci Xi™ and da Vinci SP™, respectively. Conclusions: Robotic hysterectomy without lymph node dissection appears to be a safe and effective approach for patients with early-stage endometrial cancer. The da Vinci SP offers the advantage of shorter operative times than the da Vinci Xi™. These findings support the consideration of robotic surgery as a viable option for selected patients.

Early outcomes of three new robotic surgical systems in patients undergoing hysterectomy.

New robot models, such as hinotori™, da Vinci SP™, and Hugo™, have been introduced in Japan. This study examined the surgical outcomes of these models in patients from the initial stages of their introduction to the present day.We retrospectively reviewed 36 patients with endometrial cancer or benign gynecologic disease, who underwent robotic hysterectomy using da Vinci SP™, hinotori™, or Hugo™ between March 2023 and March 2024.Robotic hysterectomy was performed using hinotori™ in 10 patients, da Vinci SP™ in 16 patients, and Hugo™ in 10 patients. No significant differences were observed in the characteristics of the patients subjected to surgery using these models. The total operative time was 123.0 min (93-144 min) for hinotori™, 95.0 min (79-165 min) for da Vinci SP™, and 98.5 min (74-177 min) for Hugo™. The total operative time of hinotori™ was significantly longer than that of the other two models (p = 0.031). No differences were observed among the robot systems with respect to complications during or after surgery and the intensity of postoperative pain.Differences in the surgical time were noted depending on the model used. It has been proven that surgeons who are already proficient in performing robotic surgery with da Vinci Xi™ can safely perform surgeries with the new models.

Placenta Percreta Progression to Resistance Against Uterine Artery Embolization and Penetration Into the Bladder.

A 31-year-old female sought termination of pregnancy due to a fetal body stalk anomaly diagnosed at 18 weeks of gestation. Despite an anterior placenta previa, successful vaginal delivery occurred. However, placental adhesion over a previous cesarean scar occurred, and part of the placenta could not be removed. Immediate postpartum bleeding prompted imaging studies, revealing extravasation from adherent placental remnants. Uterine artery embolization (UAE) provided initial hemostasis, but recurrent bleeding necessitated re-embolization. Although conservative treatment was initially pursued, significant hematuria prompted reevaluation, revealing extensive uterine wall and bladder penetration. Surgical intervention with total hysterectomy and partial bladder resection was performed, leading to the successful recovery of bladder function following surgical repair. While this case achieved a positive outcome, there is a potential for permanent urinary dysfunction if lesions are more extensive. While achieving a conservative cure is ideal, it is essential to assess the timing for opting for surgical intervention.

The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population.

Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

NTRK2 expression in gastrointestinal stromal tumors with a special emphasis on the clinicopathological and prognostic impacts.

Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin.

The interplay between the epithelial permeability barrier, cell migration and mitochondrial metabolism of growth factors and their inhibitors in a human endometrial carcinoma cell line.

It is known that there are abnormalities of tight junction functions, cell migration and mitochondrial metabolism in human endometriosis and endometrial carcinoma. In this study, we investigated the effects of growth factors and their inhibitors on the epithelial permeability barrier, cell migration and mitochondrial metabolism in 2D and 2.5D cultures of human endometrioid endometrial carcinoma Sawano cells. We also investigated the changes of bicellular and tricellular tight junction molecules and ciliogenesis induced by these inhibitors. The growth factors TGF-ß and EGF affected the epithelial permeability barrier, cell migration and expression of bicellular and tricellular tight junction molecules in 2D and 2.5D cultures of Sawano cells. EW-7197 (a TGF-ß receptor inhibitor), AG1478 (an EGFR inhibitor) and SP600125 (a JNK inhibitor) affected the epithelial permeability barrier, cell migration and mitochondrial metabolism and prevented the changes induced by TGF-ß and EGF in 2D and 2.5D cultures. EW-7197 and AG1478 induced ciliogenesis in 2.5D cultures. In conclusion, TGF-ß and EGF promoted the malignancy of endometrial cancer via interplay among the epithelial permeability barrier, cell migration and mitochondrial metabolism. EW-7197 and AG1478 may be useful as novel therapeutic treatments options for endometrial cancer.

Endocrinological and Metabolic Heterogeneity Is Low in Japanese Women With Polycystic Ovary Syndrome.

OBJECTIVES: This study aims to evaluate the endocrine differences among polycystic ovary syndrome (PCOS) phenotypes in Japanese women. METHODS: 118 Japanese women that we diagnosed with PCOS agreed to be included in the study. The study group was classified into the following 4 phenotypes: (A) hyperandrogenism (HA); ovulatory disorder (OvD) and polycystic ovary morphology (PCOM); (B) HA and OvD; (C) HA and PCOM; and (D) OvD and PCOM. We also recruited 66 healthy Japanese women to the study as control participants. Age, body mass index, androgens, luteinizing hormone, follicle-stimulating hormone, and insulin resistance (IR) index were evaluated and compared. RESULTS: The proportions of phenotypes A, B, C, and D were 57/120 (47.5%), 4/120 (3.3%), 13/120 (10.8%), and 46/120 (38.3%), respectively. The proportion of phenotype B was too small; therefore, phenotypes A and B were grouped as classical PCOS for intergroup comparisons. The luteinizing hormone/follicle-stimulating hormone ratio in the classical PCOS group was higher than that in the phenotype D group (P < 0.001). Androgen concentrations in the phenotype D group were significantly lower than those in the other groups (P < 0.01). Phenotype D was more common in lean women with PCOS. The surrogate marker of IR (homeostasis model assessment of IR) was not different irrespective of PCOS and its phenotypes. CONCLUSIONS: Except for androgens, endocrine differences by PCOS phenotype are not evident, suggesting that diversity among patients with PCOS is relatively low in Japanese women.

Pregnancy-specific beta-1-glycoprotein 6 is a potential novel diagnostic biomarker of placenta accreta spectrum.

Early diagnosis is essential for the safer perinatal management of placenta accreta spectrum (PAS). We used transcriptome analysis to investigate diagnostic maternal serum biomarkers and the mechanisms of PAS development. We analyzed eight formalin-fixed paraffin-embedded placental specimens from two placenta increta and three placenta percreta cases who underwent cesarean hysterectomy at Sapporo Medical University Hospital between 2013 and 2019. Invaded placental regions were isolated from the uterine myometrium and RNA was extracted. The transcriptome difference between normal placenta and PAS was analyzed by microarray analysis. The PAS group showed markedly decreased expression of placenta-specific genes such as LGALS13 and the pregnancy-specific beta-1-glycoprotein (PSG) family. Term enrichment analysis revealed changes in genes related to cellular protein catabolic process, female pregnancy, autophagy, and metabolism of lipids. From the highly dysregulated genes in the PAS group, we investigated the expression of PSG family members, which are secreted into the intervillous space and can be detected in maternal serum from the early stage of pregnancy. The gene expression level of PSG6 in particular was progressively decreased from placenta increta to percreta. The PSG family, especially PSG6, is a potential biomarker for PAS diagnosis.

Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma.

A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine-specific demethylase 5D (KDM5D) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia-telangiectasia and Rad3-related (ATR) inhibitor treatment. We evaluated KDM5D copy number loss in 173 surgically resected SCCs from male patients using fluorescence in situ hybridization. KDM5D copy number loss was detected in 75 of the 173 patients (43%). Genome-wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the KDM5D copy number loss are associated with 'cell cycle', whereas downregulated genes in tumors with KDM5D copy number loss were associated with 'immune response'. Clinicopathologically, SCCs with KDM5D copy number loss were associated with late pathological stage (p = 0.0085) and high stromal content (p = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor-infiltrating CD8+ /T-bet+ T cells was lower in SCCs with KDM5D copy number loss than in wild-type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited KDM5D copy number loss. Tumors in patients who show this distinct phenotype can be 'cold tumors', which are characterized by the paucity of tumor T-cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors.

Detection of Novel Tyrosine Kinase Fusion Genes as Potential Therapeutic Targets in Bone and Soft Tissue Sarcomas Using DNA/RNA-based Clinical Sequencing.

BACKGROUND: Approximately 1% of clinically treatable tyrosine kinase fusions, including anaplastic lymphoma kinase, neurotrophic tyrosine receptor kinase, RET proto-oncogene, and ROS proto-oncogene 1, have been identified in soft tissue sarcomas via comprehensive genome profiling based on DNA sequencing. Histologic tumor-specific fusion genes have been reported in approximately 20% of soft tissue sarcomas; however, unlike tyrosine kinase fusion genes, these fusions cannot be directly targeted in therapy. Approximately 80% of tumor-specific fusion-negative sarcomas, including myxofibrosarcoma and leiomyosarcoma, that are defined in complex karyotype sarcomas remain genetically uncharacterized; this mutually exclusive pattern of mutations suggests that other mutually exclusive driver oncogenes are yet to be discovered. Tumor-specific, fusion-negative sarcomas may be associated with unique translocations, and oncogenic fusion genes, including tyrosine kinase fusions, may have been overlooked in these sarcomas. QUESTIONS/PURPOSES: (1) Can DNA- or RNA-based analysis reveal any characteristic gene alterations in bone and soft tissue sarcomas? (2) Can useful and potential tyrosine kinase fusions in tumors from tumor-specific, fusion-negative sarcomas be detected using an RNA-based screening system? (3) Do the identified potential fusion tumors, especially in neurotrophic tyrosine receptor kinase gene fusions in bone sarcoma, transform cells and respond to targeted drug treatment in in vitro assays? (4) Can the identified tyrosine kinase fusion genes in sarcomas be useful therapeutic targets? METHODS: Between 2017 and 2020, we treated 100 patients for bone and soft tissue sarcomas at five institutions. Any biopsy or surgery from which a specimen could be obtained was included as potentially eligible. Ninety percent (90 patients) of patients were eligible; a further 8% (8 patients) were excluded because they were either lost to follow-up or their diagnosis was changed, leaving 82% (82 patients) for analysis here. To answer our first and second questions regarding gene alterations and potential tyrosine kinase fusions in eight bone and 74 soft tissue sarcomas, we used the TruSight Tumor 170 assay to detect mutations, copy number variations, and gene fusions in the samples. To answer our third question, we performed functional analyses involving in vitro assays to determine whether the identified tyrosine kinase fusions were associated with oncogenic abilities and drug responses. Finally, to determine usefulness as therapeutic targets, two pediatric patients harboring an NTRK fusion and an ALK fusion were treated with tyrosine kinase inhibitors in clinical trials. RESULTS: DNA/RNA-based analysis demonstrated characteristic alterations in bone and soft tissue sarcomas; DNA-based analyses detected TP53 and copy number alterations of MDM2 and CDK4 . These single-nucleotide variants and copy number variations were enriched in specific fusion-negative sarcomas. RNA-based screening detected fusion genes in 24% (20 of 82) of patients. Useful potential fusions were detected in 19% (11 of 58) of tumor-specific fusion-negative sarcomas, with nine of these patients harboring tyrosine kinase fusion genes; five of these patients had in-frame tyrosine kinase fusion genes ( STRN3-NTRK3, VWC2-EGFR, ICK-KDR, FOXP2-MET , and CEP290-MET ) with unknown pathologic significance. The functional analysis revealed that STRN3-NTRK3 rearrangement that was identified in bone had a strong transforming potential in 3T3 cells, and that STRN3-NTRK3 -positive cells were sensitive to larotrectinib in vitro. To confirm the usefulness of identified tyrosine kinase fusion genes as therapeutic targets, patients with well-characterized LMNA-NTRK1 and CLTC-ALK fusions were treated with tyrosine kinase inhibitors in clinical trials, and a complete response was achieved. CONCLUSION: We identified useful potential therapeutic targets for tyrosine kinase fusions in bone and soft tissue sarcomas using RNA-based analysis. We successfully identified STRN3-NTRK3 fusion in a patient with leiomyosarcoma of bone and determined the malignant potential of this fusion gene via functional analyses and drug effects. In light of these discoveries, comprehensive genome profiling should be considered even if the sarcoma is a bone sarcoma. There seem to be some limitations regarding current DNA-based comprehensive genome profiling tests, and it is important to use RNA testing for proper diagnosis and accurate identification of fusion genes. Studies on more patients, validation of results, and further functional analysis of unknown tyrosine kinase fusion genes are required to establish future treatments. CLINICAL RELEVANCE: DNA- and RNA-based screening systems may be useful for detecting tyrosine kinase fusion genes in specific fusion-negative sarcomas and identifying key therapeutic targets, leading to possible breakthroughs in the treatment of bone and soft tissue sarcomas. Given that current DNA sequencing misses fusion genes, RNA-based screening systems should be widely considered as a worldwide test for sarcoma. If standard treatments such as chemotherapy are not effective, or even if the sarcoma is of bone, RNA sequencing should be considered to identify as many therapeutic targets as possible.

Diagnosis and Methods of Repair for a Uteroperitoneal Fistula (UPF) Formed After Gynecological Surgeries.

A uteroperitoneal fistula (UPF) is a rare disorder that can lead to infertility and has never been reported. UPFs can cause infertility and perinatal complications. A 34-year-old woman (gravida 0) with a history of three gynecological surgeries using a uterine manipulator was diagnosed with a UPF using hysteroscopy and hysterosalpingography. She underwent laparoscopic uterine repair as an infertility treatment. The uterine perforation may have been caused by uterine manipulator insertion or suture failure in the myometrium during her previous laparoscopic myomectomy and cystectomy procedures. The UPF disappeared after the current surgical treatment. The complications of UPFs include infection, infertility, ectopic pregnancy, and uterine rupture. We expected that the presence of a fistula would increase the risk of impaired fertilization, implantation failure, and ectopic pregnancy. This case report contributes valuable insights into the diagnosis of UPFs and their laparoscopic repair.

Frequent nuclear ß-catenin expression in pulmonary enteric-type adenocarcinoma according to the current World Health Organization criteria.

Based on the current World Health Organization classification criteria, five of 3895 consecutive cases of surgically resected primary lung carcinomas (0.13%) categorized as enteric-type were analyzed. Three cases completely comprised tumor cells that resemble colorectal adenocarcinoma, while the other two cases exhibited features of conventional adenocarcinomas admixed with enteric components. Immunohistochemically, all patients expressed at least three of the five intestinal markers: CDX2, CK20, HNF4α, MUC2, and SATB2. None of the patients expressed TTF-1 and NKX3.1. Three cases showed nuclear accumulation of ß-catenin, indicating activation of the Wnt/ß-catenin signaling pathway; APC mutations were detected in one of these cases. TP53 mutations were detected in three cases. Mutated EGFR or ALK fusions were not detected. Our study demonstrates that pulmonary enteric-type adenocarcinomas share immunohistochemical features and genetic alterations with colorectal adenocarcinomas, which are characterized by frequent activation of the Wnt/ß-catenin signaling pathway and a lack of actionable mutations.

Nationwide trends in and regional factors associated with minimally invasive hysterectomy for benign indications in Japan.

OBJECTIVE: To examine the prevalence trends of minimally invasive hysterectomy for benign indications in Japan and investigate regional disparities. STUDY DESIGN: A retrospective cohort and ecological study using "The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data". SETTING: Nationwide Japan. PATIENTS: Individuals who underwent hysterectomy for benign indications from 2014 to 2020. INTERVENTIONS: Trend analysis of minimally invasive surgery (MIS) rates through laparoscopic hysterectomies (LH) and robotic-assisted laparoscopic hysterectomies (RA-LH) at the national and prefecture levels. Examination of regional factors contributing to the disparity in MIS implementation rates by second medical service area (SMSA). RESULTS: The number of LH has increased from 16,016 in 2014 to 27,755 in 2020. The nationwide MIS hysterectomy rate increased from 29% in 2014 to 55% in 2020 (p less than 0.001). More than 50% of hysterectomies have been performed as MIS since 2019. There was an increasing trend in MIS rates in all age groups. All prefectures except one showed a significant upward trend (p less than 0.05) in the MIS rates, but MIS rates varied widely (23-84%). In a multivariable model, the MIS was more likely to be performed in the SMSAs in western Japan (p = 0.011), in the SMSAs where the number of laparoscopy-qualified gynecologists is 5-10 (p = 0.013), and 11 or higher (p less than 0.001). CONCLUSIONS: This study reveals a shift towards minimally invasive surgery (MIS) in total hysterectomy procedures in Japan. However, significant disparities in the prevalence of MIS hysterectomy exist, potentially influenced by the number of laparoscopy-qualified gynecologists.

Clinicopathological characteristics of gastric adenocarcinoma with enteroblastic differentiation and gastric adenocarcinoma with enteroblastic marker expression.

Gastric adenocarcinoma (GA) with enteroblastic differentiation (GAED) is an aggressive carcinoma histologically characterized by a glycogen-rich clear cytoplasm and fetal gut-like structures. GAED shows the expression of at least one of the following enteroblastic markers (EMs): glypican-3 (GPC3), spalt-like transcription factor 4 (SALL4), and α-fetoprotein (AFP). Despite the absence of clear cytoplasm, we often encounter GA with EMs expression (GA with EM); however, the clinicopathological characteristics of GA with EM remain unclear. Immunohistochemical (IHC) expression of three EMs (AFP, GPC3, and SALL4) was examined on tissue microarray. According to the status of the clear cytoplasm of tumor cells, GAs showing IHC expression of EMs were classified as either GAED or GA with EM, and this analysis categorized 688 GAs into 94 GAEDs (13.7%), 58 GAs with EM (8.4%), and 536 conventional GAs (CGAs). Both GAED and GA with EM showed frequent lymphovascular invasion, lymph node metastasis, and liver metastasis compared to CGA. However, a higher frequency of venous invasion, but not of lymphatic invasion, was noted for GAED in comparison to CGA. GAED and GA with EM showed similar overall survival. GAED had significantly poorer prognosis than CGA; however, not for GA with EM. Furthermore, GA showing EM expression had a worse prognosis than CGA. Interestingly, GA showing EM-positive group was more aggressive than CGA group as they had frequent venous invasion and liver metastasis despite its smaller tumor size. GAED and GA with EM can be clinically classified as aggressive tumors but pathologically they seem to be slightly different.