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This study examined the risk of intrauterine infection associated with radical trachelectomy (RT) in early‐stage cervical cancer patients. This procedure preserves fertility but is linked to increased risk of intrauterine infection due to cervical defects during pregnancy. DNA was extracted from the formalin‐fixed paraffin‐embedded (FFPE) placental specimens of 23 pregnant post‐RT patients and 16S rRNA gene sequencing was used for bacterial identification. The prevalence of Lactobacillus crispatus and Burkholderia stabilis was significantly higher in the non‐chorioamnionitis group. In contrast, alpha diversity analysis using the PD index showed significantly higher diversity in the chorioamnionitis group (P = 0.04). The demonstrated relationship between chorioamnionitis and microbial diversity affirms the importance of controlling the genital bacterial flora in pregnancies following RT.

Objective: Laser vaporization is less invasive than conization for cervical intraepithelial neoplasia (CIN). The outcome of laser vaporization for CIN is empirically known to depend on the colposcopic findings, especially localization of the lesion. In this study, we sought to identify factors involved in the outcome of laser vaporization. Materials and methods: We retrospectively investigated 290 cases of CIN (CIN2, n = 180; CIN3, n = 110) treated with laser evaporation at Nishikawa Women's Health Clinic between 2018 and 2021. All treatments were performed using a carbon dioxide laser under either colposcopic vision (n = 172) or direct vision using a vaginal speculum (n = 118). Risk factors were statistically examined for cure rate after treatment. Results: Multivariate analysis using a logistic regression model identified independent factors affecting the success of treatment to be high-risk human papillomavirus infection status preoperatively, CIN grade, presence of CIN lesions at the periphery of the cervix, and the surgical method used. Colposcopy-guided laser vaporization reduced the risk of treatment failure by 84% (odds ratio 0.16, 95% confidence interval 0.06–0.46; p = 0.001) compared with direct vision using a vaginal speculum. For lesions at the periphery of the cervix, most of the treatment failures were in the group that was not guided by colposcopy (p = 0.031). Conclusion: The presence of a peripheral CIN lesion was suggested to be a risk factor for treatment failure. Laser vaporization under colposcopic vision is recommended for treatment of peripheral CIN lesions.

After the 1995 Hyogo-ken Nanbu Earthquake in Japan, rock structures, including rock slopes and underground cavities, were required to be evaluated for seismic resistance. Understanding the dynamic deformation properties of hard rock is essential for performing dynamic response analysis of large deformations of rock structures. This paper discusses the effect of confining pressure on the strain level dependence of the Young’s modulus and damping ratio of water-saturated sandstone based on the results of cyclic triaxial tests. The relationship between the axial strain and equivalent Young’s modulus ratio is different for quasi-elastic deformation below 2,000 με and elastoplastic deformation above 2,000 με and hence can be approximated by two logarithmic functions. The relationship at the quasi-elastic strain level can be approximated by the same function regardless of the confining pressure. However, at the elastoplastic strain level, the slope of the logarithmic function decreases with increasing confining pressure. Furthermore, the relationship between the axial strain and damping ratio is distributed on the same curve regardless of the confining pressure in the axial strain range below 4,000 με. However, when the axial strain exceeds 4,000 με, this relationship deviates from the curve and the damping ratio rapidly increases with decreasing confining pressure. The experimental results for water-saturated sandstone were compared with those for dry sandstone presented in a previous paper. At the quasi-elastic strain level, the relationship between the axial strain and equivalent Young’s modulus ratio can be approximated by the same function regardless of the water content. However, at the elastoplastic strain level, the slope of the logarithmic function is greater for water-saturated sandstone than for dry sandstone. Meanwhile, the relationship between the axial strain and damping ratio, regardless of the water content, is distributed on the same curve in the range from quasi-elastic to elastoplastic strain.

IntroductionMesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma that occurs at widespread anatomical locations, such as bone, soft tissue, and intracranial sites. The central nervous system (CNS) is one of the most common origins of extraosseous MCS. However, alternative HEY1::NCOA2 fusions have not been reported in this tumor.Case reportWe report a case of intracranial MCS with HEY1::NCOA2 rearrangement. A 52-year-old woman presented with a 15-mm calcified mass around the sella turcica. She initially underwent transsphenoidal surgery for tumor resection and then additional resections for five local recurrences over 5 years. Histologically, the tumor was composed of small round to spindle-shaped cells admixed with well-differentiated hyaline cartilaginous islands. A hemangiopericytoma-like vascular pattern and small sinusoid-like vessels were also observed. RNA sequencing using RNA extracted from formalin-fixed paraffin-embedded samples from the last operation revealed two alternative variants of the HEY1::NCOA2 fusion: HEY1(ex4)::NCOA2 (ex13) and HEY1(ex4)::NCOA2(ex14). Both variants were confirmed as in-frame fusions using reverse transcription-polymerase chain reaction.DiscussionCartilaginous components were often not apparent during the recurrences. In addition to the non-typical pathological finding, the correct diagnosis was hampered by the poor RNA quality of the surgical specimens and non-specific STAT6 nuclear staining.ConclusionThis is the first reported case of intracranial MCS with an alternative HEY1::NCOA2 fusion.

Abstract 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.

Uterine metastases from extragenital sites are rare. We present a case of a woman who had undergone surgery for small intestinal cancer and subsequently developed metastases in her left ovary and uterus. A nulliparous woman in her 50s underwent laparoscopic partial small bowel resection with lymph node dissection for small intestinal cancer. Five months later, computed tomography (CT) revealed a left ovarian tumor and ascites. She underwent bilateral adnexectomy and adjuvant chemotherapy, and the ovarian tumor was diagnosed as a small intestinal cancer metastasis. Two years after the small intestinal cancer surgery, a positron emission tomography (PET)-CT scan revealed a uterine accumulation. Cervical cytology was negative for intraepithelial lesion or malignancy. Endometrial histology showed an adenocarcinoma of the uterus. The patient underwent total abdominal hysterectomy followed by adjuvant chemotherapy. Histopathology and immunohistochemistry of the uterine tumor revealed that it was a metastasis of small intestinal cancer (Cytokeratin 7 [CK7] [−], Cytokeratin 20 [CK20] [+], Special AT-Rich Sequence-Binding Protein 2 [SATB2] [+], Paired Box Gene 2 [PAX2] [−], and estrogen receptor [ER] [−]). In patients with cancer, histopathology and immunohistochemistry are important for distinguishing between primary and metastatic tumors and for guiding the choice of treatment.

Abstract 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.

Objective To show how endoCUT mode can be safely managed with cervical conization. Methods Demonstration of the technique and explanation of endoCUT and soft coagulation mode with narrated video footage. Cervical conization is a therapeutic and diagnostic procedure performed for the diagnosis of cervical intraepithelial lesions and cervical cancer. Specific methods include cold scalpel, ultrasonically activated device and laser, and loop electrosurgical excision procedure (LEEP), which involves transpiration and partial excision. The endoCUT mode and soft coagulation in VIO3® (ERBE, Tübingen, Germany) were used to perform cervical conical resection safely and at low cost. The endoCUT mode was originally developed for polypectomy in gastrointestinal endoscopy, where no counter traction can be applied. Results The endoCUT mode approach to cervical conization with several key strategies to minimize blood loss and ensure safety: 1) incisions can be made in close contact; 2) resection can be performed with minimal contact with the lesion; 3) control of bleeding from the resected transection by soft coagulation; and 4) low running cost of endoCUT mode. Conclusion Conventionally, cervical conical resection has been performed by using a device capable of making a close incision (cold scalpel, ultrasonically activated device and laser, and LEEP etc.), but there have been issues with bleeding control and cost. Here, we present a new technique using the endoCUT mode and several strategies for safe and effective resection.

Abstract Background Thymic squamous cell carcinoma and type B3 thymoma are primary neoplasms of the anterior mediastinum that are sometimes difficult to differentiate from one another histologically. However, only a few immunohistochemical markers are available for the differential diagnosis. The purpose of this study was to discover a novel marker for differentiating between thymic squamous cell carcinoma and type B3 thymoma. Methods We used histological samples of thymic carcinomas (n = 26) and type B3 thymomas (n = 38) which were resected between 1986 and 2017. To search for candidates of differential markers, gene expression levels were evaluated in samples using promoter analysis by cap analysis of gene expression (CAGE) sequencing. Results Promoter level expression of CALML5 genes was significantly higher in thymic carcinomas than in type B3 thymomas. We further validated the results of the CAGE analysis in all 26 thymic carcinomas and 38 type B3 thymomas by immunohistochemistry (IHC). CALML5 was strongly expressed in the cytoplasm in 19 of 26 cases with thymic carcinoma, whereas positivity at the protein level was shown in two of 38 type B3 thymomas. Thus, the sensitivity (73.1%) and specificity (94.7%) of CALML5 as markers for immunohistochemical diagnosis of thymic carcinoma were extremely high. Conclusion We identified CALML5 as a potential marker for differentiating thymic squamous cell carcinoma from type B3 thymoma. It is assumed that future clinical use of CALML5 may improve the diagnostic accuracy of differentiating between these two diseases.

Abstract Adjuvant chemotherapy has played a major role in the treatment of hormone receptor-positive breast cancer for many years. To better determine which patient subsets need adjuvant chemotherapy, various gene expression analyses have been developed, but cost-effective tools to identify such patients remain elusive. In the present report, we retrospectively investigated immunohistochemical expression and subcellular localization of MUC1 in primary tumors and examined their relationship to tumor malignancy, chemotherapy effect and patient outcomes. We retrospectively examined three patient cohorts with hormone receptor-positive/human epidermal growth factor receptor 2-negative invasive breast cancer: 51 patients who underwent 21-gene expression analysis (multi-gene assay-cohort), 96 patients who received neoadjuvant chemotherapy (neoadjuvant chemotherapy-cohort), and 609 patients whose tumor tissue was used in tissue-microarrays (tissue-microarray-cohort). The immunohistochemical staining pattern of the anti-MUC1 monoclonal antibody, Ma695, was examined in cancer tissues, and subcellular localization was determined as apical, cytoplasmic or negative. In the multi-gene assay-cohort, tumors with apical patterns had the lowest recurrence scores, reflecting lower tumor malignancy, and were significantly lower than MUC1-negative tumors (P = 0.038). In the neoadjuvant chemotherapy-cohort, there was no correlation between MUC1 staining patterns and effects of chemotherapy. Finally, in the tissue-microarray-cohort, we found that patients with apical MUC1 staining patterns had significantly longer disease-free-survival and overall survival than other patterns (P = 0.020 and 0.039, respectively). Our data suggest that an apical MUC1 staining pattern indicates luminal A-likeness. Assessment of the subcellular localization of MUC1 glycoprotein may be useful for identifying patients who can avoid adjuvant chemotherapy.

Abstract Background One cause of the increase in cervical cancer rates in Japan is the long-term stagnation in the cervical cancer screening consultation rate. Therefore, improving the screening consultation rate is of urgent concern to reduce cervical cancer incidence. Self-collected human papilloma virus (HPV) tests have been successfully adopted in several countries, such as the Netherlands and Australia, as a measure of individuals who have not undergone cervical cancer screening in national programs. This study aimed to verify whether self-collected HPV tests presented an effective countermeasure for individuals who had not undergone the recommended cervical cancer screenings. Methods This study was conducted from December 2020 to September 2022 in Muroran City, Japan. The primary evaluated endpoint was the percentage of citizens who underwent cervical cancer screening at a hospital with positive self-collected HPV test results. The secondary endpoint was the percentage of included participants who were diagnosed with cervical intraepithelial neoplasia (CIN) or higher among those who visited a hospital and underwent cervical cancer screening. Results The included study participants were 7,653 individuals aged 20–50 years with no record of previous cervical cancer examination in the past 5 years. We mailed these participants information on self-administered HPV tests as an alternative screening procedure and sent the kit to 1,674 women who requested the test. Among them, 953 returned the kit. Among the 89 HPV-positive individuals (positive rate, 9.3%), 71 (79.8%) visited the designated hospital for an examination. A closer examination revealed that 13 women (18.3% of hospital visits) had a CIN finding of CIN2 or higher, among whom one each had cervical cancer and vulvar cancer, eight presented with CIN3, and three presented with CIN2; two cases of invasive gynecologic cancer were also identified. Conclusions We conclude that the self-collected HPV tests showed a certain efficacy as a measure of individuals who had not undergone the recommended cervical cancer screening. We devised ways to have the unexamined patients undergo HPV testing and ensure that HPV-positive individuals visited the hospital. Despite a few limitations, our findings suggest the effectiveness of this public health intervention.

Abstract Background A paradigm shift has occurred in cancer chemotherapy from tumor‐specific treatment with cytotoxic agents to personalized medicine with molecular‐targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary‐sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions. Methods This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations. Results The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden‐high (TMB‐H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non‐small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%). Conclusion The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine.

Abstract Introduction Histiocytic sarcoma (HS) is a rare hematologic malignancy. HS of the breast is extremely rare, and we present a case of an elderly patient with breast HS. Case presentation An 81-year-old woman with unremarkable past medical and family histories presented to our hospital with a palpable mass in her right upper breast. She had noticed a mass in her right breast 3 months before her first visit. Physical examination revealed a mass measuring approximately 30 mm in the right upper quadrant of the breast; there were no cervical or axillary lymphadenopathies. Mammography revealed a high-concentration mass with unclear margins in the upper and outer breast. Ultrasound and magnetic resonance imaging (MRI) revealed a 31 × 23-mm nodule with a relatively clear margin and necrotic sign on the T2-intensified image. A mastectomy was performed upon the patient’s request, and the surgical specimen revealed a 35-mm hemorrhagic mass. The lesion was estrogen receptor-, progesterone receptor-, and HER2/neu-negative. The Ki-67 labeling index was approximately 30%. The immunohistochemical panel showed immune reactivity for the histiocytic markers CD68, CD163, and CD206 and was immune-negative for B lineage, T lineage, Langerhans cells, and keratins. The diagnosis of HS was based on the morphological and immunophenotypic characteristics of the mass. The patient received no systemic therapy and survived for 50 months without recurrence. Conclusions Here, we report the case of an elderly patient with rare breast HS. Although the prognosis of HS seems poor, the breast HS was not as poor as expected, since it might have been discovered in the local region before it metastasized.

Background and Aims: Eosinophils are present in several solid tumors and have context-dependent function. Our aim is to define the contribution of eosinophils in esophageal squamous cell carcinoma (ESCC), as their role in ESCC is unknown. Methods: Eosinophils were enumerated in tissues from 2 ESCC cohorts. Mice were treated with 4-NQO for 8 weeks to induce precancer or 16 weeks to induce carcinoma. The eosinophil number was modified by a monoclonal antibody to interleukin-5 (IL5mAb), recombinant IL-5 (rIL-5), or genetically with eosinophil-deficient (ΔdblGATA) mice or mice deficient in eosinophil chemoattractant eotaxin-1 (Ccl11–/–). Esophageal tissue and eosinophil-specific RNA sequencing was performed to understand eosinophil function. Three-dimensional coculturing of eosinophils with precancer or cancer cells was done to ascertain direct effects of eosinophils. Results: Activated eosinophils are present in higher numbers in early-stage vs late-stage ESCC. Mice treated with 4-NQO exhibit more esophageal eosinophils in precancer vs cancer. Correspondingly, epithelial cell Ccl11 expression is higher in mice with precancer. Eosinophil depletion using 3 mouse models (Ccl11–/– mice, ΔdblGATA mice, IL5mAb treatment) all display exacerbated 4-NQO tumorigenesis. Conversely, treatment with rIL-5 increases esophageal eosinophilia and protects against precancer and carcinoma. Tissue and eosinophil RNA sequencing revealed eosinophils drive oxidative stress in precancer. In vitro coculturing of eosinophils with precancer or cancer cells resulted in increased apoptosis in the presence of a degranulating agent, which is reversed with NAC, a reactive oxygen species scavenger. ΔdblGATA mice exhibited increased CD4 T cell infiltration, IL-17, and enrichment of IL-17 protumorigenic pathways. Conclusion: Eosinophils likely protect against ESCC through reactive oxygen species release during degranulation and suppression of IL-17.

Abstract Background Letrozole has been reported to be effective in treating anovulation, preventing ovarian hyperstimulation syndrome (OHSS), and retrieving oocytes in breast cancer patients. However, the role and mechanism of letrozole in follicular development remain unclear. Results We treated mouse preantral follicles with various treatments; we found no significant difference in follicle survival rates in the letrozole (LET) group compared with the control group, but the average diameter of follicles in the LET group tended to be larger (CTRL vs. LET 30, p = 0.064; CTRL vs. LET 100, p = 0.025). The estradiol concentrations in culture media of the LET group were significantly lower than those observed in the control group (CTRL vs. LET 30, p = 0.038; CTRL vs. LET 100, p = 0.025). We further found a marked increase in follicle-stimulating hormone receptor (FSHR) gene expression in response to letrozole treatment (CTRL vs. LET 30, p = 0.075; CTRL vs. LET 100, p = 0.034). This result suggested that increased FSHR expression promotes follicle development. Letrozole inhibited aromatase activity, but the effect was limited. Letrozole did not significantly reduce vascular endothelial growth factor (VEGF) gene expression. Conclusions Letrozole may promote follicle development by increasing the expression of FSHR. Letrozole may be useful for fertility preservation of patients with estrogen-dependent cancers such as breast cancer and various other cancers. Whether letrozole has a direct effect in reducing OHSS requires further investigation.

Purpose: To gauge the effects of treatment practices on prognosis for older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This is a prospective cohort study which accompanies the RESPECT that is a randomized-controlled trial (RCT). Methods: Patients who declined the RCT were treated based on the physician's discretion. We studied the 1) trastuzumab-plus-chemotherapy group, 2) trastuzumab-monotherapy group, and 3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were assessed. Results: We enrolled 123 patients aged over 70 years (median: 74.5). Treatment categories were: trastuzumab-plus-chemotherapy group (n = 36, 30%), trastuzumab-monotherapy group (n = 52, 43%), and non-trastuzumab group (n = 32, 27%). The 3-year DFS was 96.7% in trastuzumab-plus-chemotherapy group, 89.2% in trastuzumab-monotherapy group, and 82.5% in non-trastuzumab group. DFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted hazard ratio; HR: 3.29; 95% CI: 1.15–9.39; P = 0.026). The RFS in non-trastuzumab group was lower than in trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P

Abstract Background and Aim Juvenile polyposis (JP) is a rare disease known to be associated with mutations either in SMAD4/BMPR1A. JP is known to often develop into malignant tumors, with a reported probability of 9–50%. However, the mechanisms of its carcinogenesis are not fully understood. We tried to elucidate the mechanisms of malignant transformation underlying this condition in three cases of gastric JP. Methods We selected polyps from each patient displaying varying degrees of atypia and their nearby normal polyps and compared them using immunohistochemistry, Sanger sequencing, and loss of heterozygosity (LOH) analysis of SMAD4, BMPR1A, and TP53. Results Two of the three cases were suspected of having germline SMAD4 mutations based on their familial medical histories; the remaining case was found to have a SMAD4 germline mutation following preoperative genetic testing. All three cases were shown to present with both SMAD4 positive and negative areas across each lesion, with the neoplastic lesions tending to show stronger nuclear SMAD4 expression. This expression was closely associated with the SMAD4 LOH status; however, we also noted paradoxical SMAD4 expression in the neoplastic lesions despite the biallelic inactivation of SMAD4 revealed in the genetic evaluation. Conclusions These data suggest that strong nuclear expression of SMAD4, even when seemingly paradoxical, seems to be closely associated with dysplastic polyps in JP. Complete inactivation of SMAD4 was not shown to be essential for the development of dysplastic polyps in gastric JP, and other pathways seemed to be involved in the acquisition of the malignant phenotype.

Uterine leiomyosarcoma (LMS) is a gynecological malignancy with an extremely poor prognosis. Multiple new therapeutic agents, including pazopanib, trabectedin, and eribulin, have been clinically applied to treat uterine LMS, and their therapeutic effects are expected. We encountered one patient with advanced recurrent uterine LMS who achieved a partial response to a four-year treatment with eribulin. A 31-year-old woman was diagnosed with stage 2B LMS. After the first recurrence, Gemcitabine, Docetaxel (GD) therapy was administered, and complete response (CR) was achieved. However, 2 years and 10 months later, recurrence occurred at the vaginal cuff, and GD therapy and doxorubicin hydrochloride were administered, resulting in CR. Five months later, she experienced another recurrence at the same location and was treated with eribulin. To date, 53 courses of eribulin have been administered and are currently ongoing. Maintaining low neutrophil-to-lymphocyte ratio and low platelet-to lymphocyte ratio in this manner is considered to be one of the reasons why eribulin continues to be effective. We encountered a rare case in which eribulin was administered for the longest period of time, and produced an observable effect in uterine LMS.

Abstract Background Although many cervical cytology diagnostic support systems have been developed, it is challenging to classify overlapping cell clusters with a variety of patterns in the same way that humans do. In this study, we developed a fast and accurate system for the detection and classification of atypical cell clusters by using a two‐step algorithm based on two different deep learning algorithms. Methods We created 919 cell images from liquid‐based cervical cytological samples collected at Sapporo Medical University and annotated them based on the Bethesda system as a dataset for machine learning. Most of the images captured overlapping and crowded cells, and images were oversampled by digital processing. The detection system consists of two steps: (1) detection of atypical cells using You Only Look Once v4 (YOLOv4) and (2) classification of the detected cells using ResNeSt. A label smoothing algorithm was used for the dataset in the second classification step. This method annotates multiple correct classes from a single cell image with a smooth probability distribution. Results The first step, cell detection by YOLOv4, was able to detect all atypical cells above ASC‐US without any observed false negatives. The detected cell images were then analyzed in the second step, cell classification by the ResNeSt algorithm, which exhibited average accuracy and F‐measure values of 90.5% and 70.5%, respectively. The oversampling of the training image and label smoothing algorithm contributed to the improvement of the system's accuracy. Conclusion This system combines two deep learning algorithms to enable accurate detection and classification of cell clusters based on the Bethesda system, which has been difficult to achieve in the past. We will conduct further research and development of this system as a platform for augmented reality microscopes for cytological diagnosis.

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor. However, the therapeutic results of the advanced cases at the first visit were still extremely poor. Therefore, more effective therapeutic options based on molecular profiling of OS are needed. In this study, we investigated the functions of endoplasmic reticulum (ER) stress activities in OS and elucidated whether ER stress inhibitors could exert antitumor effects. The expression of 84 key genes associated with unfolded protein response (UPR) was assessed in four OS cells (143B, MG63, U2OS and KHOS) by RT2 Profiler PCR Arrays. Based on results, we performed both siRNA and inhibitor assays focusing on IRE1α-XBP1 and PERK pathways. All OS cell lines showed resistance to PERK inhibitors. Furthermore, ATF4 and EIF2A inhibition by siRNA did not affect the survival of OS cell lines. On the other hand, IRE1α-XBP1 inhibition by toyocamycin suppressed OS cell growth (IC50:

Introduction Comprehensive analyses using clinical sequences subcategorized osteosarcoma (OS) into several groups according to the activated signaling pathways. Mutually exclusive co-occurrences of gene amplification ( PDGFRA/KIT/KDR, VEGFA/CCND3, and MDM2/CDK4 ) have been identified in approximately 40% of OS, representing candidate subsets for clinical evaluation of additional therapeutic options. Thus, it would be desirable to evaluate the specific gene amplification before starting therapy in patients with OS. Materials and Methods This is a retrospective study. We examined 13 cases of clinical OS samples using NanoString-based copy number variation (CNV) analysis. Decalcification and chemotherapeutic effects on this analysis were also assessed. Results First, the accuracy of this system was validated by showing that amplification/deletion data obtained from this system using various types of cancer cell lines almost perfectly matched to that from the Cancer Cell Line Encyclopedia (CCLE). We identified potentially actionable alterations in CDK4/MDM2 amplification in 10% of samples and potential additional therapeutic targets ( PDGFRA/KIT/KDR and VEGFA/CCND3 ) in 20% of samples, which is consistent with the reported frequencies. Furthermore, this assay could identify these potential therapeutic targets regardless of the sample status (frozen vs formalin-fixed paraffin-embedded [FFPE] tissues). Conclusion We established a NanoString-based rapid and cost-effective method with a short turnaround time (TAT) to examine gene amplification status in OS. This CNV analysis using FFPE samples is recommended where the histological evaluation of viable tumor cells is possible, especially for tumors after chemotherapy with higher chemotherapeutic effects.

Abstract There are multiple transcription start sites (TSSs) in agreement with multiple transcript variants encoding different isoforms of NKX2‐1/TTF‐1 (thyroid transcription factor 1); however, the clinicopathological significance of each transcript isoform of NKX2‐1/TTF‐1 in lung adenocarcinoma (LAD) is unknown. Herein, TSS‐level expression of NKX2‐1/TTF‐1 isoforms was evaluated in 71 LADs using bioinformatic analysis of cap analysis of gene expression (CAGE)‐sequencing data, which provides genome‐wide expression levels of the 5′‐untranslated regions and the TSSs of different isoforms. Results of CAGE were further validated in 664 LADs using in situ hybridisation. Fourteen of 17 TSSs in NKX2‐1/TTF‐1 (80% of known TSSs in FANTOM5, an atlas of mammalian promoters) were identified in LADs, including TSSs 1–13 and 15; four isoforms of NKX2‐1/TTF‐1 transcripts (NKX2‐1_001, NKX2‐1_002, NKX2‐1_004, and NKX2‐1_005) were expressed in LADs, although NKX2‐1_005 did not contain a homeodomain. Among those, six TSSs regulated NKX2‐1_004 and NKX2‐1_005, both of which contain exon 1. LADs with low expression of isoforms from TSS region 11 regulating exon 1 were significantly associated with poor prognosis in the CAGE data set. In the validation set, 62 tumours (9.3%) showed no expression of NKX2‐1/TTF‐1 exon 1; such tumours were significantly associated with older age, EGFR wild‐type tumours, and poor prognosis. In contrast, 94 tumours, including 22 of 30 pulmonary invasive mucinous adenocarcinomas (IMAs) exhibited exon 1 expression without immunohistochemical TTF‐1 protein expression. Furthermore, IMAs commonly exhibited higher exon 1 expression relative to that of exon 4/5, which contained a homeodomain in comparison with EGFR‐mutated LADs. These transcriptome and clinicopathological results reveal that LAD use at least 80% of NKX2‐1 TSSs and expression of the NKX2‐1/TTF‐1 transcript isoform without exon 1 (NKX2‐1_004 and NKX2‐1_005) defines a distinct subset of LAD characterised by aggressive behaviour in elder patients. Moreover, usage of alternative TSSs regions regulating NKX2‐1_005 may occur in subsets of LADs.

Summary: Background: There is no effective treatment for women with unexplained recurrent pregnancy loss (RPL). We aimed to investigate whether treatment with a high dose of intravenous immunoglobulin (IVIG) in early pregnancy can improve pregnancy outcomes in women with unexplained RPL. Methods: In a double-blind, randomised, placebo-controlled trial, women with primary RPL of unexplained aetiology received 400 mg/kg of IVIG daily or placebo for five consecutive days starting at 4–6 weeks of gestation. They had experienced four or more miscarriages except biochemical pregnancy loss and at least one miscarriage of normal chromosome karyotype. The primary outcome was ongoing pregnancy rate at 22 weeks of gestation, and the live birth rate was the secondary outcome. We analysed all women receiving the study drug (intention-to-treat, ITT) and women except those who miscarried due to fetal chromosome abnormality (modified-ITT). This study is registered with ClinicalTrials.gov number, NCT02184741. Findings: From June 3, 2014 to Jan 29, 2020, 102 women were randomly assigned to receive IVIG (n = 53) or placebo (n = 49). Three women were excluded; therefore 50 women received IVIG and 49 women received placebo in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (31/50 [62·0%] vs. 17/49 [34·7%]; odds ratio [OR] 3·07, 95% CI 1·35–6·97; p = 0·009) and the live birth rate (29/50 [58·0%] vs. 17/49 [34·7%]; OR 2·60, 95% CI 1·15–5·86; p = 0·03) in the IVIG group were higher than those in the placebo group in the ITT population. The ongoing pregnancy rate at 22 weeks of gestation (OR 6·27, 95% CI 2·21–17·78; p

Intimal sarcoma arising from the tunica intima of both systemic and pulmonary circulations is a rare disorder, whereas intimal sarcoma with chondroblastic osteosarcomatous differentiation (ISCOS) is even rarer. We present the case of a 25-year-old woman with ISCOS of the pulmonary artery (PA) where the patient went through surgical treatment after careful imaging assessment under a rather emergent situation. A 25-year-old Japanese female presented to our hospital with the chief complaints of dyspnea and palpitations on exertion. Upon arrival, she had systolic murmur, moderate tricuspid regurgitation, and possible pulmonary hypertension. A contrast-enhanced chest computed tomography (CT) showed dilatation of the main PA, filled with a hypodense area with calcification adjacent to the right and left PA. The calcified lesions within the tumor were the key findings suggesting osteoid-forming sarcoma, differentiating it from pulmonary embolism. Due to presence of critical symptomatic obliteration of the pulmonary circulation, an emergency surgery was performed. A whitish shiny mass filled the lumens from the main PA to the bilateral main PAs. The tumor was not attached to the surrounding intima, except for a slight attachment to the left interlobar PA, and could be completely removed from the vessel lumen. Based on the pathological findings, it was diagnosed as a primary ISCOS of the PA, which correlated with the findings of the CT, namely intratumoral calcification. Although the diagnosis-making is quite challenging, multidisciplinary collaboration between clinicians, radiologists, and pathologists is crucial for reaching the correct diagnosis.

Abstract NTRK fusion-positive tumors are known to be highly sensitive to TRK inhibitors, such as larotrectinib and entrectinib. Therefore, identification of patients who can potentially benefit from these inhibitors is important; however, the frequency of NTRK fusions in Japanese patients with colorectal cancer (CRC) is unknown. We performed pan-TRK staining using TMA-based immunohistochemistry (IHC) on samples from 971 consecutive Japanese CRC cases from a single institution. Positive cases were further analyzed using NanoString and subsequent targeted RNA sequencing. We found three positive cases using TRK-IHC. Furthermore, the Nanostring assay supported the presence of NTRK fusion in these cases. Subsequent targeted RNA-sequencing and RT-PCR revealed two cases with TPM3-NTRK1 and one with TPR-NTRK1. The TNM stages of these cases were stage I, stage IIA, and stage IIIB, and two showed microsatellite instability-high status. Next-generation sequencing analysis using Cancer hotspot panel revealed TP53 and SMAD4 mutations in separate cases. IHC of β-catenin did not show nuclear accumulation. We found three cases (0.31%) of CRC with NTRK1 fusion among 971 consecutive Japanese CRC cases. No potential driver alterations other than NTRK fusion were identified in these three patients.

Background: Chemotherapy-induced peripheral neuropathy is commonly observed in patients treated with nanoparticle albumin–bound paclitaxel (nab-PTX). We conducted a multicenter randomized controlled study to evaluate the optimal dose of nab-PTX. Methods: We compared three different doses of q3w nab-PTX (Standard: 260 mg/m2 [SD260] vs Medium: 220 mg/m2 [MD220] vs Low: 180 mg/m2 [LD180]) in patients with HER2-negative metastatic breast cancer (MBC). Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses were estimated using the logistic regression model. The optimal dose was selected in two steps. Initially, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was excluded, and we proceeded with the non-inferior dose. Then, if the estimated incidence rate of grade 3/4 neurotoxicity exceeded 10%, that dose was also excluded. Results: One hundred forty-one patients were randomly assigned to SD260 (n = 47), MD220 (n = 46), and LD180 (n = 48) groups, and their median PFS was 6.66, 7.34, and 6.82 months, respectively. The HRs were 0.73 (95% confidence interval [CI]: 0.42–1.28) in MD220 vs SD260, 0.77 (95% CI 0.47–1.28) in LD180 vs SD260, and 0.96 (95% CI 0.56–1.66) in LD180 vs MD220. SD260 was inferior to MD220 and was excluded. The estimated incidence rate of grade 3/4 neurotoxicity was 29.5% in SD260, 14.0% in MD220, and 5.9% in LD180. The final selected dose was LD180. Conclusions: Intravenous administration of low-dose nab-PTX at 180 mg/m2 q3w may be the optimal therapy with meaningful efficacy and favorable toxicity in patients with MBC.

Cervical varix during pregnancy is a rare condition, and standard management for bleeding from a varix has not been established. We performed cross double cervical cerclage and effectively stopped bleeding. A 41-year-old female had a twin pregnancy. The development of a cervical varix was observed during pregnancy and bleeding from ruptured varix started at 20 weeks of gestation. We performed surgical hemostasis by cervical cerclage. In the first cerclage, we could not stop the bleeding from the varix. For further restriction of blood supply to the cervical varix, we performed a second cerclage in a crossed position on a deeper side of the vagina than the first cerclage. Then the bleeding completely stopped and there was no bleeding until delivery. The “cross double McDonald cerclage” performed in our patient may be a useful modified cerclage method for stopping intractable bleeding from the cervix during pregnancy.

Abstract Background Peritoneal carcinoma is a rare disease that is diagnosed and treated in a manner similar to ovarian cancer. In most cases, the histological type is serous carcinoma, and chemotherapy is effective. However, there are a few case reports of mucinous peritoneal carcinoma. We inferred the histological type before surgery using an ascites cell block sample, which was useful for determining the treatment plan. Case presentation Our patient was a 60-year-old Japanese woman. She presented with a feeling of fullness in the abdomen. A computed tomographic scan showed a large quantity of ascitic fluid and thickening of the greater omentum, as well as thickening of the peritoneum at the pouch of Douglas and diaphragm. Hence, peritoneal carcinoma was suspected. The tumor markers carcinoembryonic antigen, cancer antigen 19-9, and cancer antigen 125 were all increased, and no malignant findings were observed in the uterus or ovaries. Cells suggestive of carcinoma were found in the ascitic fluid, and immunostaining by the cell block method suggested the possibility of mucinous carcinoma. The preoperative chemotherapy strategy was changed to short courses, and tumor reduction surgery was planned. Similar to the suspicion before surgery, the pathology results indicated mucinous carcinoma, and the therapeutic effect of chemotherapy was grade 0. Conclusions Determining whether peritoneal carcinoma is serous carcinoma is important for therapy and prognostic prediction. In this case, we encountered a patient for whom surgery was chosen because of drug therapy resistance inferred through histological type estimation using the cell block method. Inferring the histological type by cell block preparation is useful for diagnosis and treatment selection.

Abstract Background Radical tracheletomy (RT) with pelvic lymphadenectomy has become an option for young patients with early invasive uterine cervical cancer who desire to maintain their fertility. However, this operative method entails a high risk for the following pregnancy due to its radicality. Methods We have performed vaginal RT for 71 patients and have experienced 28 pregnancies in 21 patients. They were followed up carefully according to the follow-up methods we reported previously. Their pregnancy courses and prognoses after the pregnancy were retrospectively reviewed. Results All the vaginal RTs were performed safely without serious complications, including 6 patients who underwent the operation during pregnancy. The median time to be pregnant after RT was 29.5 months. 13 patients (46%) became pregnant without artificial insemination by husband or assisted reproductive technology. Cesarean section was performed for all of them. The median time of pregnancy was 34 weeks, and emergent cesarean section was performed for 7 pregnancies (25%). The median birth weight was 2156 g. Four patients had trouble with cervical cerclage, and they suffered from sudden premature preterm rupture of the membrane (pPROM) during the second trimester of pregnancy. We underwent transabdominal cerclage (TAC) for all of them and careful management for the prevention of uterine infection was performed. One patient had a recurrence of cancer during pregnancy. Conclusions Both the obstetrical prognosis and oncological prognosis after vaginal RT have become favorable for pregnant patients after vaginal RT.

Ehlers-Danlos syndrome is a rare genetic disorder that presents with a variety of pathologies depending on the disease type. Among them, vascular Ehlers-Danlos syndrome requires extremely careful management as there have been many reports of fatal perinatal complications such as uterine rupture. Although hypermobile Ehlers-Danlos syndrome is less likely to cause fatal complications, symptoms such as arthralgia, hip dislocation, and depression may be seen throughout pregnancy. We report here a case of twin pregnancy in which Ehlers-Danlos syndrome was first suspected at 19 weeks of gestation. Vascular Ehlers-Danlos syndrome could not be ruled out based on family medical history, making it difficult to determine the perinatal management strategy. Prompt genetic testing did however rule out the vascular type and the patient was diagnosed with hypermobile Ehlers-Danlos syndrome from the clinical symptoms, enabling us to manage the pregnancy safely until 34 weeks of gestation.

Toward clarifying the biomechanics and neural mechanisms underlying coordinated control of the complex hand musculoskeletal system, we constructed an anatomically based musculoskeletal model of the Japanese macaque (Macaca fuscata) hand, and then estimated the muscle force of all the hand muscles during a precision grip task using inverse dynamic calculation. The musculoskeletal model was constructed from a computed tomography scan of one adult male macaque cadaver. The hand skeleton was modeled as a chain of rigid links connected by revolute joints. The path of each muscle was defined as a series of points connected by line segments. Using this anatomical model and a model-based matching technique, we constructed 3D hand kinematics during the precision grip task from five simultaneous video recordings. Specifically, we collected electromyographic and kinematic data from one adult male Japanese macaque during the precision grip task and two sequences of the precision grip task were analyzed based on inverse dynamics. Our estimated muscular force patterns were generally in agreement with simultaneously measured electromyographic data. Direct measurement of muscle activations for all the muscles involved in the precision grip task is not feasible, but the present inverse dynamic approach allows estimation for all the hand muscles. Although some methodological limitations certainly exist, the constructed model analysis framework has potential in clarifying the biomechanics and neural control of manual dexterity in macaques and humans.

Recently, radical vaginal hysterectomy (RVH) has developed into laparoscopically assisted radical vaginal hysterectomy (LARVH), which is associated with the laparoscopical procedure, and it is applied as radical vaginal trachelectomy and semi-radical vaginal hysterectomy. LARVH is indicated for patients with stage IB1 and IIA1 cervical carcinoma, especially those with a tumor size of less than 2 cm, because the cardinal ligaments cannot be resected widely. Although RVH that is associated with laparoscopic pelvic lymphadenectomy is the most used surgical procedure, radical trachelectomy may be performed either abdominally or vaginally (laparoscopic or robotic). One report found that the pregnancy rate was higher in patients who underwent minimally invasive or radical vaginal trachelectomy than in those who underwent radical abdominal trachelectomy.

Inflammatory fibroid polyp (IFP) is a rare and benign tumor of the gastrointestinal (GI) tract that harbors PDGFRA mutations. PDGFRA alterations are also found in subsets of other GI tract mesenchymal tumors, such as KIT-negative gastrointestinal stromal tumors and inflammatory myofibroblastic tumors. We report a case of ileal IFP with uncommon histological features. A 71-year-old woman was referred to our hospital with abdominal pain. She was diagnosed with intestinal intussusception. Laparoscopic surgery was performed and the ileum was resected by 50 cm. Microscopically, tumor cells with round nuclei and prominent nucleoli proliferating within the collagenous fibrous stroma were observed. Some spindle-shaped cells and lymphoplasmacytic infiltrations were also observed, and eosinophils were scattered throughout the lesion. Lymphovascular structures of various sizes were prominent in the stroma. Immunohistochemistry revealed PDGFRA overexpression but did not show positive staining for CD34. The tumor had a heterozygous deletion of five amino acids in exon 12 (del 1696-1710, Δ566-570) of PDGFRA. Based on these findings, a diagnosis of IFP was made. The patient remains alive without any evidence of recurrence.

Uterine adenomyosis often co-occurs with endometriosis or leiomyoma, but little is known about its molecular underpinnings. Here, the authors show that KRAS mutations are frequent in this disease, which might reduce sensitivity to progestin treatment via epigenetic silencing of the progesterone receptor.

Abstract Purpose To evaluate the efficacy of silicone sheet as a new type of barrier for preventing adhesion reformation following hysteroscopic adhesiolysis of intrauterine adhesions (IUAs). Methods Hysteroscopic adhesiolysis was performed for 36 patients with IUAs. The adhesion reformation rate was retrospectively compared between 26 patients treated with silicone sheet (group 1) and 10 patients treated with an intrauterine device wrapped in oxidized regenerated cellulose as a barrier (group 2). For patients in group 1, a 1‐mm‐thick silicone sheet was cut to fit the size and shape of the individual uterine cavity as a personalized barrier. Results The size and shape of each silicone sheet used for patients in group 1 differed significantly. The adhesion reformation rate was significantly lower in group 1 (4/26, 15.4%) than in group 2 (4/10, 40.0%; P = 0.03), although the pregnancy rate (14/20, 70.0% vs. 5/10, 50.0%; P = 0.28) and miscarriage rate (2/14, 14.3% vs. 1/5, 20.0%; P = 0.72) were not significantly different. Conclusion Use of silicone sheets appears to be effective for preventing adhesion reformation following hysteroscopic adhesiolysis of IUAs. This is the first study to investigate the efficacy of silicone sheet used as a personalized barrier for preventing IUAs.

Abstract Polycystic ovary syndrome (PCOS) is an endocrine disease that is common in women in their reproductive period. Patients with this disease suffer from anovulation and hyperandrogenism. Ovulation induction with exogenous gonadotropin often causes ovarian hyperstimulation syndrome because many small antral follicles pause in their growth. Treatment with insulin sensitizers is reportedly effective for both anovulation associated with PCOS, and suppression of excessive follicular growth; however, the underlying mechanism of action remains unknown. Although pioglitazone is known as an insulin sensitizer, it also has a potent modulator of cell growth and apoptosis irrespective of insulin resistance. To clarify the effect of pioglitazone on follicular growth, we performed in vitro culture of murine preantral follicles. Secondary follicles (100-160 μm in diameter) isolated from 6-week-old ICR mice were individually cultured for 13 days. Culture conditions were as follows: 1) follicle-stimulating hormone (FSH; 33 mIU/mL; control), 2) FSH plus dihydrotestosterone (DHT; 500 ng/mL), 3) FSH plus pioglitazone (5 ng/mL), and 4) FSH plus DHT/pioglitazone. Survival rate and follicle diameter were evaluated, and concentrations of estradiol (E2) and vascular endothelial growth factor (VEGF) in culture media were measured. mRNA expression of various growth-promoting factors and Vegf within follicles were also assessed. Although no significant differences were observed with regard to survival rate, follicle diameters on day 13 were significantly different. Compared with the control group, the DHT group showed enhanced growth, while groups administered pioglitazone showed stagnation of the accelerated growth induced by DHT. Although DHT treatment enhanced the expression of bone morphogenetic protein 2 (Bmp2) mRNA, pioglitazone exposure suppressed induction of Bmp2 mRNA by DHT. Vegf mRNA and protein expression were also significantly reduced when pioglitazone was added to culture media containing DHT. Administration of pioglitazone negatively affected follicular growth and VEGF levels, which may suppress excessive follicular growth and prevent ovarian hyperstimulation syndrome.

Abstract Hyperandrogenism is one of the cardinal symptoms in polycystic ovary syndrome and plays a key role in the pathogenesis of polycystic ovary syndrome. However, the precise effects and mechanisms of excess androgen during follicular development are still unclear. Here we investigated the effects of androgen on mouse follicle development in vitro. Androgen did not affect the growth of follicles smaller than 160–180 μm in the presence of follicle-stimulating hormone (FSH). However, in the presence of low FSH, androgen supported the growth of follicles larger than 160–180 μm, a size at which growing follicles acquire FSH-dependency. Androgen did not change the mRNA expression of various growth-promoting factors but did increase mRNA expression of the FSH receptor. We suggest that androgen has a positive impact on follicle development by augmentation of the actions of FSH. Therefore, FSH-responsive but FSH-independent follicles grow in the presence of a certain level of FSH or androgen, and androgen compensates for FSH deficiency in FSH-dependent follicles.

A cesarean scar can cause abnormal uterine bleeding including prolonged menstruation or postmenstrual spotting. Our patient showed massive uterine bleeding from a cesarean scar and needed blood transfusion for hemorrhagic shock. A cesarean section had only been performed once for delivery stop 9 years ago. Recurrent hemorrhage could not be controlled by conservative treatment, and we performed laparoscopic scar resection and repair. The abnormal uterine bleeding was successfully stopped, and the menstrual cycle was normalized after surgical treatment. We should be aware that even an uneventful cesarean section may have a risk of massive hemorrhage postoperatively as in the present case.

Nodular fasciitis is often misdiagnosed as its histological mimics, including malignant tumors, due to high levels of cellularity and the presence of occasional mitotic figures. A 15-year-old boy noticed a mass on his left shoulder and was admitted to the hospital. Based on magnetic resonance imaging (MRI) results, the lesion seemed to be located within the muscle, just below the subcutaneous adipose tissue and adjacent to the periosteum of the left humerus. It showed an iso-low signal on T1-weighted images, a heterogeneously high signal on T2-weighted images, and a hyperintense signal on T2 fat-suppression. A fascial tail sign was observed in T2 and T2 fat-suppression sagittal slices. Although the lesion was diagnosed as nodular fasciitis by biopsy, the lesion gradually increased in size up to 3.7 cm during 2 months of follow up after the first admission. The lesion was surgically resected with the marginal margin. Histological analysis showed fascicular proliferation of spindle-shaped cells with inflammatory infiltrates and stromal bleeding. A diagnosis of nodular fasciitis was confirmed by the detection of an MYH-USP6 fusion transcript. The identification of this fusion gene helped to avoid an unnecessary surgical procedure. The patient has been followed up for 6 months after surgery without any evidence of recurrence.

Purpose: Giant cell tumor of bone (GCTB) is a local aggressive bone tumor, histologically classified as intermediate malignancy. Recently, the RANKL inhibitor, denosumab, was developed as a novel and effective treatment option for GCTB. Since the risk of preoperative use of denosumab with curettage had been previously reported, this study aimed to investigate the relationship between recurrences and clinicopathological features associated with adjuvant denosumab treatment in GCTB. Methods: A total of 87 GCTB cases were treated at our institution. We reviewed 66 patients with conventional-type GCTB occurring in the extremities and analyzed 78 surgical treatments, including curettages and resections, with clinicopathological features and denosumab treatment. Results: GCTB lesions, including 66 primary and 12 recurring, underwent surgical treatment like curettage and resection. Recurrence-free survivals in 78 GCTB surgeries were 78.7% in 3 years and 71.9% in 5 years. In the resected cases of GCTBs, there was no recurrence either with or without denosumab. In curettage cases, 3-year recurrence-free survivals were 0.0% ( n = 3) in preoperative treatment of denosumab, 66.7% ( n = 6) in postoperative treatment, and 76.6% ( n = 43) in no treatment. Interestingly, three preoperative treatment cases demonstrated low MIB-1 index despite 100% recurrence. The other clinicopathological factors did not contribute much to the risk of recurrence in curettage cases. Conclusion: Our findings revealed the use of denosumab in GCTB, prior to curettage, to possibly increase the risk of local recurrence. Together with previous reports, our finding might provide information for beneficial treatment of GCTB.

Abstract Background Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. Methods We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. Results Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. Conclusions SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.

Abstract Case A 32 year old woman was referred because of secondary amenorrhea, hirsutism, and voice deepening. Outcome The blood testosterone level was markedly high. A transvaginal ultrasound revealed a small region in the left ovary, but whether or not it was a tumor was unclear. Therefore, selective ovarian venous sampling was performed. Consequently, the testosterone level was selectively increased in a blood sample that was taken from the left ovarian vein, the tumor was successfully localized, and a laparoscopic left oophorectomy was performed. Although the left ovary appeared to be normal at laparoscopy, the androgen‐secreting tumor was located within it. The tumor was diagnosed as a Leydig cell tumor by histopathological analyses. Conclusion This report demonstrates that selective blood sampling from ovarian veins before an operation is effective in localizing an androgen‐producing ovarian tumor that is difficult to diagnose by imaging studies.

Objective: Umbilical cord entanglement is known to be a major cause of fetal hypoxia and to be correlated with several neonatal complications, but almost all of the previous reports were restricted to nuchal cord. In this study, we retrospectively examined the correlation between multiple part cord entanglement and pregnancy outcomes. Materials and methods: A total of 2156 cases were recruited from term deliveries in our hospital from 2008 to 2012. We counted umbilical cord loop numbers not only for nuchal cord but also for trunk and limb cord entanglement. We classified the cases into three groups: no loop, single loop and multiple loops group. We statistically analyzed pregnancy outcomes statistically in the three groups. Results: One thousand, four hundred and fifty-eight cases had no cord entanglement, 594 cases had single loop entanglement and 104 cases had multiple loops entanglement. Values of umbilical artery blood, pH (p = 0.002) and base excess (p

Cervical adenocarcinomas are believed to lose estrogen response on the basis of no expression of a nuclear estrogen receptor such as ERα in clinical pathology. Here, we demonstrated that cervical adenocarcinoma cells respond to a physiological concentration of estrogen to upregulate claudin-1, a cell surface molecule highly expressed in cervical adenocarcinomas. Knockout of claudin-1 induced apoptosis and significantly inhibited proliferation, migration, and invasion of cervical adenocarcinoma cells and tumorigenicity in vivo. Importantly, all of the cervical adenocarcinoma cell lines examined expressed a membrane-bound type estrogen receptor, G protein–coupled receptor 30 (GPR30/GPER1), but not ERα. Estrogen-dependent induction of claudin-1 expression was mediated by GPR30 via ERK and/or Akt signaling. In surgical specimens, there was a positive correlation between claudin-1 expression and GPR30 expression. Double high expression of claudin-1 and GPR30 predicts poor prognosis in patients with cervical adenocarcinomas. Mechanism-based targeting of estrogen/GPR30 signaling and claudin-1 may be effective for cervical adenocarcinoma therapy.

Abstract Background To examine the efficacy and safety of induction therapy with paclitaxel and bevacizumab followed by switch maintenance therapy with eribulin (ISMT) in Japanese patients with HER2-negative metastatic breast cancer (MBC). Methods Patients, who had previously undergone a maximum of 2 regimens of chemotherapy, received 3 cycles of induction therapy with paclitaxel (90 mg/m2 intravenously on days 1, 8, and 15 followed by 1-week drug holiday) and bevacizumab (10 mg/kg intravenously after the completion of paclitaxel administration on days 1 and 15). Patients who had complete response, partial response, or stable disease underwent switch maintenance therapy with eribulin (1.4 mg/m2 intravenously on days 1 and 8 followed by 1-week drug holiday). The primary endpoint was time to treatment failure (TTF) for ISMT. Results Fifty-one eligible patients (median age: 66 years; range: 35–74) were enrolled: 19 (37.3%) and 32 (62.7%) had stage IV and recurrence, respectively, 42 (82.4%) had visceral metastases, and 45 (88.2%) received eribulin—38 of whom showed disease progression, and 40 (78.4%) underwent post therapy. Median TTF was 9.2 months (95% confidence interval [CI]: 7.3–11.1), median progression-free survival was 10.7 months (95% CI: 9.6–11.8), and median overall survival was 20.0 months (95% CI: 16.0–24.0). Relative dose intensity was 97.7% (range: 33.3–100.0) for induction therapy and was 83.3% (range: 49.3–100.6%) for eribulin maintenance therapy. The most common adverse event was alopecia (51 [100%]) in induction therapy and was peripheral sensory neuropathy (37 [82.2%]) in eribulin maintenance therapy. Eribulin was effective with manageable tolerability. Conclusions ISMT may be a promising therapeutic option for patients with MBC. Trial registration UMIN000015971. Registration date: January 1, 2015.

Abstract Background Hyperandrogenism and insulin resistance may be related to the etiology of PCOS. Zucker fa/fa rats with polycystic ovary are obese, have insulin resistance without diabetes mellitus or hyperandrogenism and can be utilized as PCOS model rats without effects of hyperandrogenemia. PCOS patients are reported to have elevated levels of serum anti-Mullerian hormone (AMH), which has an inhibitory action on folliculogenesis, and low levels of serum adiponectin, which blocks apoptosis and induces biological effects in some tissues. Pioglitazone, an insulin sensitizer, is administered to PCOS patients with insulin resistance to induce ovulation but the mechanisms by which this occurs have not been elucidated. Methods We purchased 4-week-old female fatty Zucker fa/fa rats as well as lean Zucker +/+ rats for use as control rats with normal insulin sensitivity. The Zucker fa/fa rats were administered pioglitazone (2.5 mg/kg body weight/day) or a vehicle every day for 14 days in separate groups. The Zucker +/+ rats were also administered the vehicle. After 2 weeks of treatment, they were euthanized and we obtained serum samples and both ovaries and determined the body weight, ovarian weight, and serum AMH, adiponectin, testosterone, and androstenedione levels. We also examined ovarian histology to check follicle numbers by using hematoxylin-eosin staining, and the number of atretic follicles using Tdt-mediated dUTP nick end labeling (TUNEL) methods. Results The Zucker fa/fa rats used as PCO model rats and Pioglitazone treated PCO model rats were significantly heavier than the Zucker +/+ control rats (p

Objective: Hereditary antithrombin (AT) deficiency increases the risk of venous thromboembolism (VTE) in pregnant woman. We report the first case of administration of recombinant human antithrombin (rhAT) to a pregnant Japanese woman with AT deficiency. Case report: A 30-year-old woman, gravida 2 para 0, was referred to our hospital because of AT deficiency. Unfractionated heparin was administered from 13 weeks of gestation and rhAT was administered from labor onset. A cesarean section was performed and the patient and her baby were healthy, with no sequelae. Conclusion: We concluded that rhAT was effective for preventing VTE during delivery, with no potential infection risks. Keywords: Hereditary antithrombin deficiency, Pregnancy, Prophylaxis, Recombinant human antithrombin, Venous thromboembolism