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Abstract. When an exotic hadron locates near the threshold with the channel couplings, the internal structure of the exotic hadron is related to the scattering length. To incorporate the threshold effect, the Flatté amplitude has been often used to determine the scattering length. It is however known that an additional constraint is imposed on the Flatte amplitude near the threshold. We discuss this problem by using the effective field theory for the coupled-channel scattering.

The efflux ratio (ER), determined by Caco-2/MDCK assays, is the standard in vitro metric to establish qualitatively whether a compound is a substrate of an efflux transporter. However, others have also enabled the utilisation of this metric quantitatively by deriving a relationship that expresses the ER as a function of the intrinsic membrane permeability of the membrane (P0) as well as the permeability of carrier-mediated efflux (Ppgp). As of yet, Ppgp cannot be measured directly from transport experiments or otherwise, but the ER relationship provides easy access to this value if P0 is known. However, previous derivations of this relationship failed to consider the influence of additional transport resistances such as the aqueous boundary layers (ABLs) and the filter on which the monolayer is grown. Since single fluxes in either direction can be heavily affected by these experimental artefacts, it is crucial to consider the potential impact on the ER. We present a model that includes these factors and show both mathematically and experimentally that this simple ER relationship also holds for the more realistic scenario that does not neglect the ABLs/filter. Furthermore, we also show mathematically how paracellular transport affects the ER, and we experimentally confirm that paracellular dominance reduces the ER to unity and can mask potential efflux.

Background/aim: Nestin, an intermediate filament protein expressed in stem/progenitor cells of the developing central nervous system, is involved in the progression and poor prognosis of various malignancies. Difficulties in small-cell lung cancer (SCLC) tissue biopsy reduce the accuracy of immunohistochemistry analyses; therefore, evaluating nestin in blood samples is preferred in clinical practice. This study examined the clinical significance of plasma nestin levels in SCLC., Patients and Methods: A single-center observational study of patients with untreated SCLC was conducted from 2019 to 2021. We determined plasma nestin levels before and after two treatment cycles, and the results were analyzed in relation to clinical outcome., Results: Twenty-five SCLC patients were enrolled. When patients were divided into high-plasma nestin (h-pNES) and low-plasma nestin (l-pNES) groups based on pre-treatment plasma nestin levels, among nine extensive-stage SCLC (ES-SCLC) patients treated with immune checkpoint inhibitor (ICI) combination chemotherapy, h-pNES patients had shorter progression-free survival and overall survival than l-pNES patients (p=0.0150 and p=0.0353, respectively). CD8/FoxP3- and CD8/CD3-positive T-cell ratios in biopsy specimens from h-pNES patients were lower than those of l-pNES patients (p=0.0458 and p=0.0218, respectively)., Conclusion: This pilot study indicated that h-pNES patients exhibited a poorer response to ICI combination chemotherapy than l-pNES patients. Plasma nestin levels are easy to measure in ES-SCLC, in which sufficient tissue is difficult to obtain, and may potentially serve as a predictor of response to ICI combination chemotherapy. A large cohort is needed to investigate the clinical role of plasma nestin., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV2) infection has forced social changes worldwide. Development of potent antiviral agents is necessary to prevent future pandemics. Titanium oxide, a photocatalyst, is a long-acting antiviral agent; however, its effects are weakened in the dark. Therefore, new antiviral substances that can be used in the dark are needed. Two types of nitroxyl radicals, 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) and 2-azaadamantane N-oxyl (AZADO), are commonly used as oxidation catalysts utilizing oxygen in the air as the terminal oxidant. Therefore, in this study, we aimed to evaluate the potential of these radicals as antiviral compounds with sustained activity even in the dark. We evaluated the antiviral effects of oxoammonium salts corresponding to TEMPO and AZADO (TEMPO-Oxo and AZADO-Oxo, respectively), which are the active forms of nitroxyl radicals in oxidation reactions. TEMPO-Oxo and AZADO-Oxo inhibited the binding of SARS-CoV2 spike protein receptor-binding domain (S-RBD) to angiotensin-converting enzyme 2. Notably, AZADO-Oxo exhibited a 10-fold stronger inhibitory effect than TEMPO-Oxo. TEMPO-Oxo and AZADO-Oxo also denatured S-RBD; however, effects of AZADO-Oxo were 10-fold stronger than those of TEMPO-Oxo and did not change in the dark. Some S-RBD peptides treated with AZADO-Oxo were cleaved at the N-terminal side of tyrosine residues. TEMPO-Oxo and AZADO-Oxo exhibited concentration-dependent antiviral effects against feline coronavirus. In conclusion, active forms of the nitroxyl radicals, TEMPO-Oxo and AZADO-Oxo, exerted antiviral effects by denaturing S-RBD, regardless of the presence or absence of light, suggesting their potential as novel antiviral agents., (© 2024. The Author(s).)

Purpose: Enlargement of the trigeminal nerve is observed in 20-53% of patients with IgG4-related ophthalmic disease (IgG4-ROD) and is known to be a useful finding for the diagnosis of IgG4-ROD. On the other hand, enlargement of the trigeminal nerve has also been found at a certain frequency in orbital lymphoproliferative diseases other than IgG4-ROD. Therefore, we here re-evaluated the specificity of trigeminal nerve enlargement in the diagnosis of IgG4-ROD., Study Design: Retrospective, comparative study., Methods: A total of 149 consecutive cases of IgG4-ROD diagnosed at the Department of Ophthalmology, Tokyo Medical University Hospital were studied. As controls, 218 cases of orbital lymphoma, 13 cases of reactive lymphoid hyperplasia (RLH), and 117 cases of benign orbital tumors other than lymphoproliferative diseases were included. Enlargement of the trigeminal nerve (infraorbital or supraorbital nerve) in IgG4-ROD and all the control cases was evaluated on MRI or CT coronal images., Results: Enlargement of the trigeminal nerve was observed in 35 of the 149 cases (23.5%) of IgG4-ROD and in 7 of the 218 cases (3.2%) of lymphoma, with a significantly highly frequency in IgG4-ROD (P < .0001). No cases of trigeminal nerve enlargement were observed in the cases of RLH or benign orbital tumors. The sensitivity and the specificity of trigeminal nerve enlargement in the diagnosis of IgG4-ROD were 23.5% and 96.8%, respectively. Additionally, enlargement of the trigeminal nerve was significantly more common in men than in women (P < .028)., Conclusions: The present study indicates that trigeminal nerve enlargement is a characteristic imaging finding and has diagnostic value for IgG4-ROD., (© 2024. Japanese Ophthalmological Society.)

Susceptibility of human cells to cold stress restricts the use of therapeutic hypothermia and long-term preservation of organs at low temperatures. In contrast, cells of mammalian hibernators possess remarkable cold resistance, but little is known about the molecular mechanisms underlying this phenomenon. In this study, we conducted a gain-of-function screening of genes that confer cold resistance to cold-vulnerable human cells using a cDNA library constructed from the Syrian hamster, a mammalian hibernator, and identified Gpx4 as a potent suppressor of cold-induced cell death. Additionally, genetic deletion of or pharmacological inhibition of Gpx4 revealed that Gpx4 is necessary for suppressing lipid peroxidation specifically under cold in hamster cell lines. Genetic disruption of other ferroptosis-suppressing pathways, namely biopterin synthesis and mitochondrial or plasma membrane CoQ reduction pathways, also accelerated cold-induced cell death under Gpx4 dysfunction. Collectively, ferroptosis-suppressing pathways protect the cells of a mammalian hibernator from cold-induced cell death and the augmentation of these pathways renders cold resistance to cells of non-hibernators, including humans., (© 2024. The Author(s).)

Objectives: To elucidate the outcomes of periviable infants receiving active care (AC) and explore perinatal factors associated with neurodevelopmental outcomes., Methods: This is a single-center retrospective study on infants born at 22-25 weeks of gestation, all of whom received AC. A developmental quotient (DQ) ≥ 85 at corrected 18 months was judged as normal., Results: Fifty-seven infants were included in the study. The survival rates at discharge were 83%, 86%, 93%, and 93% at 22, 23, 24, and 25 gestational weeks, respectively. The overall percentage of normal DQ was 26/47 (55%). Acidemia in the arterial blood gas measured within 6 h after birth was identified as a factor significantly associated with subnormal DQ., Conclusions: Not only high survival rates, but also favorable neurodevelopmental outcomes may be achieved by AC in periviable infants. Moreover, impaired neurodevelopmental outcomes may be associated with early postnatal acidemia following initial resuscitation., (© 2024. The Author(s).)

A Japanese clinical trial (JGOG3016) showed that dose-dense weekly paclitaxel in combination with carboplatin extensively prolonged overall survival (OS) in patients with advanced ovarian cancer. However, in other clinical trials, dose-dense paclitaxel regimens were not superior to triweekly paclitaxel regimens. In this study, causal tree analysis was applied to explore subpopulations with different treatment effects of dose-dense paclitaxel in a data-driven approach. The 587 participants with stage II-IV ovarian cancer in the JGOG3016 trial were used for model development. The primary endpoint was treatment effect in terms of 3-year OS in patients receiving dose-dense vs. conventional paclitaxel therapies. In patients <50 years, the 3-year OS was similar in both groups; however, it was higher in the dose-dense group in patients ≥50 years. Dose-dense paclitaxel showed strong positive treatment effects in patients ≥50 years with stage II/III disease, BMI <23 kg/m 2 , non-CC/MC, and residual tumor ≥1 cm. In contrast, although there was no significant difference in OS; the 3-year OS rate was 23% lower in dose-dense paclitaxel than conventional paclitaxel in patients ≥60 years with stage IV cancer. Patients in this group had a particularly lower performance status than other groups. Our causal tree analysis suggested that poor prognosis groups represented by residual tumor tissue ≥1 cm benefit from dose-dense paclitaxel, whereas elderly patients with advanced disease and low-performance status are negatively impacted by dose-dense paclitaxel. These subpopulations will be of interest to future validation studies. Personalized treatments based on clinical features are expected to improve advanced ovarian cancer prognosis., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Objective: Patients with ovarian clear cell carcinoma (OCCC) often present with thrombosis. While cancer patients with concomitant thrombosis were generally reported to have worse prognoses than those without, the association between thrombosis and prognosis has not been elucidated in OCCC. This study aimed to determine how the co-occurrence of thrombosis affects OCCC prognoses., Methods: We retrospectively examined 115 patients with OCCC who were diagnosed and treated at the University of Tokyo Hospital between 2009 and 2019., Results: Of 115 patients with OCCC, thrombosis was present in 12.5% of 80 patients and in 42.8% of 35 patients who had OCCC stage I/II and stage III/IV, respectively. In stage I/II, the 5-year progression-free survival was 20.6% and 91.8% among patients with thrombosis and among those without, respectively, while the corresponding 5-year overall survival rates were 50.0% and 94.1%. Therefore, the outcomes were significantly poorer among patients with thrombosis (p < 0.0001 and p < 0.0001, respectively). In stage III/IV, the 5-year progression-free survival was 26.7% and 52.8% among patients with thrombosis and among those without, respectively, while the corresponding 5-year overall survival rates were 32.0% and 62.2%. Similarly, the outcomes were significantly poorer among patients with thrombosis (p = 0.0139 and p = 0.369, respectively)., Conclusion: We determined that thrombosis is more likely to develop in advanced OCCC stages than in early stages, and its co-occurrence is associated with a poor prognosis, regardless of disease stage., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The cellular origin of clear cell ovarian carcinoma (CCOC), a major histological subtype of ovarian carcinoma remains elusive. Here, we explored the candidate cellular origin and identify molecular subtypes using integrated genomic/epigenomic analysis. We performed whole exome-sequencing, microarray, and DNA methylation array in 78 CCOC samples according to the original diagnosis. The findings revealed that ARID1A and/or PIK3CA mutations were mutually exclusive with DNA repair related genes, including TP53, BRCA1, and ATM. Clustering of CCOC and other ovarian carcinomas (n = 270) with normal tissues from the fallopian tube, ovarian surface epithelium, endometrial epithelium, and pelvic peritoneum mesothelium (PPM) in a methylation array showed that major CCOC subtypes (with ARID1A and/or PIK3CA mutations) were associated with the PPM-lile cluster (n = 64). This cluster was sub-divided into three clusters: (1) mismatch repair (MMR) deficient with tumor mutational burden-high (n = 2), (2) alteration of ARID1A (n = 51), and (3) ARID1A wild-type (n = 11). The remaining samples (n = 14) were subdivided into (4) ovarian surface epithelium-like (n = 11) and (5) fallopian tube-like (considered as high-grade serous histotype; n = 3). Among these, subtypes (1-3) and others (4 and 5) were found to be associated with immunoreactive signatures and epithelial-mesenchymal transition, respectively. These results contribute to the stratification of CCOC into biological subtypes., (© 2024. The Author(s).)

Human papillomavirus (HPV) is a major cause of cervical cancer. As the natural history of HPV-associated cervical lesions is HPV genotype-dependent, it is important to understand the characteristics of these genotypes and to manage them accordingly. Among high-risk HPVs, HPV16 and 18 are particularly aggressive, together accounting for 70% of HPV genotypes detected in cervical cancer. Other than HPV16 and 18, HPV31, 33, 35, 45, 52, and 58 are also at a high risk of progression to cervical intraepithelial neoplasia (CIN)3 or higher. Recent studies have shown that the natural history of HPV16, 18, 52, and 58, which are frequently detected in Japan, depends on the HPV genotype. For example, HPV16 tends to progress in a stepwise fashion from CIN1 to CIN3, while HPV52 and 58 are more likely to persist in the CIN1 to CIN2 state. Among the high-risk HPVs, HPV18 has some peculiar characteristics different from those of other high-risk HPV types; the detection rate in precancerous lesions is much lower than those of other high-risk HPVs, and it is frequently detected in highly malignant adenocarcinoma and small cell carcinoma. Recent findings demonstrate that HPV18 may be characterized by latent infection and carcinogenesis in stem cell-like cells. In this context, this review outlines the natural history of HPV-infected cervical lesions and the characteristics of each HPV genotype., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen-presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen-presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen-presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA-B alleles had a higher HPV antigen-presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2-3) than in cervicitis or early-stage CIN (CIN1): around half of CIN2-3 had LOH of any HLA class I. Moreover, the antigen-presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA-B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long-term infection and progression to advanced lesions., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Magnetic resonance imaging (MRI) is efficient for the diagnosis of preoperative uterine sarcoma; however, misdiagnoses may occur. In this study, we developed a new artificial intelligence (AI) system to overcome the limitations of requiring specialists to manually process datasets and a large amount of computer resources., Methods: The AI system comprises a tumor image filter, which extracts MRI slices containing tumors, and sarcoma evaluator, which diagnoses uterine sarcomas. We used 15 types of MRI patient sequences to train deep neural network (DNN) models used by tumor filter and sarcoma evaluator with 8 cross-validation sets. We implemented tumor filter and sarcoma evaluator using ensemble prediction technique with 9 DNN models. Ten tumor filters and sarcoma evaluator sets were developed to evaluate fluctuation accuracy. Finally, AutoDiag-AI was used to evaluate the new validation dataset, including 8 cases of sarcomas and 24 leiomyomas., Results: Tumor image filter and sarcoma evaluator accuracies were 92.68% and 90.50%, respectively. AutoDiag-AI with the original dataset accuracy was 89.32%, with 90.47% sensitivity and 88.95% specificity, whereas AutoDiag-AI with the new validation dataset accuracy was 92.44%, with 92.25% sensitivity and 92.50% specificity., Conclusion: Our newly established AI system automatically extracts tumor sites from MRI images and diagnoses them as uterine sarcomas without human intervention. Its accuracy is comparable to that of a radiologist. With further validation, the system could be applied for diagnosis of other diseases. Further improvement of the system's accuracy may enable its clinical application in the future., Competing Interests: K. Sone has a joint research agreement with SIOS Technology Incorporated. The remaining authors have no competing interests to disclose., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Ulipristal (UPA), a selective progesterone receptor modulator, has both agonistic and antagonistic effects on progesterone receptors. UPA suppresses ovulation by inhibiting the luteinizing hormone (LH) surge from the pituitary gland; however, the direct effect of UPA on ovarian tissue remains poorly studied. In the present study, we examined the effects of UPA on the ovaries of rats. Rats were treated for 28 days with UPA, and the effects of UPA on ovarian tissue were examined histologically and the expression of antioxidant genes and cell death markers were also investigated. UPA treatment increased the number of primordial follicles at each treatment group, primordial follicles increased at all dose levels, but the size/magnitude of the effect decreased with the increasing dose. The number of primary and antral follicles tended to increase with increasing UPA levels. Furthermore, the decrease in primary follicle number could be attributed to the exhaustion of follicles, but the examination of proliferation markers, oxidative stress markers, and cell death markers revealed no remarkable toxic effects on ovarian tissues. These results suggest that UPA treatment promotes follicle development at each stage but inhibits ovulation by suppressing the LH surge, resulting in an increase in atretic follicles or unruptured luteinized cysts. These results suggest that UPA may not have both toxic effects on the ovary and a direct local effect on ovarian follicles, but we should be careful about the effects of prolonged UPA treatment in patients with uterine fibroids on their future fecundity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Osamu Wada-Hiraike reports financial support was provided by ASKA Pharmaceutical Co., Ltd. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: The effectiveness of hysteroscopy in diagnosing endometrial lesions has been demonstrated, showing high diagnostic accuracy for malignant endometrial lesions. Although the characteristic appearances of atypical and malignant endometria have been reported, they are not definitive and sometimes complicated. This study aimed to identify a small number of characteristic features to detect endometrial abnormalities using a simple judgment system and analyze the diagnostic characteristics and their accuracy in endometrial malignancy diagnosis., Methods: We performed a retrospective analysis of hysteroscopy video data of 250 patients, of which we selected for analysis based on pathology examination 152 cases with benign changes, 16 with atypical endometrium, and 18 with carcinoma in situ or endometrial cancer. Endometrial characteristics assessed included protrusion, desquamation, extended vessel, atypical vessel, and white/yellow lesion., Results: Multivariable analysis revealed that desquamation (p = 0.001, odds ratio [OR] 5.28), atypical vessels (p < 0.001, OR 8.50), and white/yellow lesions (p = 0.011, OR 1.37) were significant predictors for endometrial malignancy. From their contribution status, scoring points of 4, 6, and 1 were settled according to the odds ratio proportions. When scores ≥5 (at least both desquamation and white/yellow lesions or only atypical vessels) were used to define endometrial malignancy, sensitivity and specificity were 100% and 92%, respectively. When detecting cancer, atypical, and benign cases, sensitivity and specificity were 88% and 90%, respectively., Conclusion: Our characteristics hysteroscopic findings showed a higher predictive ability in detecting endometrial malignancies. However, further examination with more cases would be needed to accurately diagnose endometrial malignancy by hysteroscopy., (© 2024 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Blood glucose levels fluctuate during daily life, and the oxygen concentration is low compared to the atmosphere. Vascular endothelial cells (ECs) maintain vascular homeostasis by sensing changes in glucose and oxygen concentrations, resulting in collective migration. However, the behaviors of ECs in response to high-glucose and hypoxic environments and the underlying mechanisms remain unclear. In this study, we investigated the collective migration of ECs simultaneously stimulated by changes in glucose and oxygen concentrations. Cell migration in EC monolayer formed inside the media channels of microfluidic devices was observed while varying the glucose and oxygen concentrations. The cell migration increased with increasing glucose concentration under normoxic condition but decreased under hypoxic condition, even in the presence of high glucose levels. In addition, inhibition of mitochondrial function reduced the cell migration regardless of glucose and oxygen concentrations. Thus, oxygen had a greater impact on cell migration than glucose, and aerobic energy production in mitochondria plays an important mechanistic role. These results provide new insights regarding vascular homeostasis relative to glucose and oxygen concentration changes., (© 2024. The Author(s).)

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi‑omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP‑seq) and RNA sequencing (RNA‑seq). The expression of PRMT6 in EC was analyzed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6‑knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP‑seq of H3K27ac antibodies and RNA‑seq. Finally, the downstream targets identified by multi‑omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6‑KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP‑seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA‑seq data demonstrated altered interferon‑related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide‑3‑kinase regulatory subunit 1, following PRMT6‑KD. RT‑qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6‑KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

Aim: We aimed to investigate the associations of endometriosis and adenomyosis with pregnancy complications by using a large-scale Japanese database., Methods: We retrospectively analyzed 145 590 singleton pregnancies from the Japan Perinatal Registry Network Database. Pregnant women registered as having endometriosis or adenomyosis were designated as the case group (EA), whereas the control group (non-EA) was selected using propensity-score matching adjusted for variables such as age, parity, BMI, smoking history, and the use of assisted reproductive technology. The main outcomes included placental malposition, preterm birth, and hypertensive disorders of pregnancy (HDP)., Results: In total, 1203 patients from both the EA and non-EA groups were matched and evaluated. The EA group showed significantly higher rates of placenta previa (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.84-4.92), low-lying placenta (OR, 2.02; 95% CI, 1.06-3.86), and preterm birth (OR, 1.44; 95% CI, 1.13-1.84) than the non-EA group. However, no significant difference was observed in the incidence of HDP (OR, 1.22; 95% CI, 0.90-1.66)., Conclusion: The use of propensity-score matching to analyze a nationwide perinatal database in Japan clarified that EA was associated with increased pregnancy complications, specifically placental malposition, including placenta previa and low-lying placenta, and preterm birth, but not with HDP., (© 2023 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Stochastic processes are commonly used models to describe dynamics of a wide variety of nonequilibrium phenomena ranging from electrical transport to biological motion. The transition matrix describing a stochastic process can be regarded as a non-Hermitian Hamiltonian. Unlike general non-Hermitian systems, the conservation of probability imposes additional constraints on the transition matrix, which can induce unique topological phenomena. Here, we reveal the role of topology in relaxation phenomena of classical stochastic processes. Specifically, we define a winding number that is related to topology of stochastic processes and show that it predicts the existence of a spectral gap that characterizes the relaxation time. Then, we numerically confirm that the winding number corresponds to the system-size dependence of the relaxation time and the characteristic transient behavior. One can experimentally realize such topological phenomena in magnetotactic bacteria and cell adhesions.

Glaucoma is one of the leading causes of acquired blindness and characterized by retinal ganglion cell (RGC) death. MicroRNAs are small noncoding RNAs that degrade their target mRNAs. Apoptosis is one of the common mechanisms leading to neuronal death in many neurodegenerative diseases, including glaucoma. In the present study, we identified microRNAs that modulate RGC death caused by the intravitreal injection of N -methyl-d-aspartic acid (NMDA). We found an upregulation of miR-29b and downregulation of miR-124 in the retina of the NMDA-injected eyes. The intravitreal injection of an miR-29b inhibitor 18 h before NMDA injection reduced RGC death and the downregulation of myeloid cell leukemia 1 (MCL-1), an anti-apoptotic factor, induced by intravitreal NMDA. The intravitreal injection of an miR-124 mimic 18 h before NMDA injection also reduced RGC death and the upregulation of B-cell/chronic lymphocytic leukemia lymphoma 2 (bcl-2)-associated X protein (Bax) and bcl-2 interacting protein (Bim), pro-apoptotic factors, induced by intravitreal NMDA. These data suggest that expressional changes in microRNA are involved in the excitotoxicity of RGCs, and that complement and/or inhibition of microRNA may be a potential therapeutic approach for the diseases related to the excitotoxicity of RGCs, such as glaucoma and retinal central artery occlusion.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high-risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR-GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR-GFP vectors were transduced into patient-derived squamocolumnar junction organoids, and the presence of GFP-positive cells was evaluated. Single-cell RNA sequencing of GFP-positive and GFP-negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP-positive and GFP-negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP-positive cells, whereas keratinization and mitophagy/autophagy-related pathways were upregulated in GFP-negative cells. siRNA-mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV-related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18-infected cells downregulated stem cell-related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18-infected cervical lesions., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

This study aimed to comprehensively clarify the genomic landscape and its association with tumor mutational burden-high (TMB-H, ≥10 mut/Mb) and microsatellite instability-high (MSI-H) in endometrial, cervical, and ovarian cancers. We obtained genomic datasets of a comprehensive genomic profiling test, FoundationOne ® CDx, with clinical information using the "Center for Cancer Genomics and Advanced Therapeutics" (C-CAT) database in Japan. Patients can undergo the tests only after standardized treatments under universal health insurance coverage. Endometrial cancers were characterized by a high frequency of TMB-H and MSI-H, especially in endometrioid carcinomas. The lower ratio of POLE exonuclease mutations and the higher ratio of TP53 mutations compared to previous reports suggested the prognostic effects of the molecular subtypes. Among the 839 cervical cancer samples, frequent mutations of KRAS , TP53 , PIK3CA , STK11 , CDKN2A , and ERBB2 were observed in adenocarcinomas, whereas the ratio of TMB-H was significantly higher in squamous cell carcinomas. Among the 1606 ovarian cancer samples, genomic profiling of serous, clear cell, endometrioid, and mucinous carcinomas was characterized. Pathogenic mutations in the POLE exonuclease domain were associated with high TMB, and the mutation ratio was low in both cervical and ovarian cancers. The C-CAT database is useful for determining the mutational landscape of each cancer type and histological subtype. As the dataset is exclusively collected from patients after the standardized treatments, the information on "druggable" alterations highlights the unmet needs for drug development in major gynecological cancers.

Objectives: Adenomyosis is associated with unfavorable perinatal outcomes, and recent case reports show that some women with adenomyosis experience pain at the adenomyosis lesion during pregnancy and have detrimental perinatal outcomes. This study aimed to clarify the clinical characteristics of this pain and perinatal outcomes associated with this phenomenon., Methods: This was a single-center retrospective analysis of pregnant women with adenomyosis. The incidence of pain onset at adenomyosis lesions, defined as persistent pain at the adenomyosis site with administration of analgesics for pain relief, and its association with perinatal outcomes were analyzed., Results: Among 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2 %) presented with pain. One pregnancy resulted in second-trimester miscarriage, and 5 of the 11 pregnancies (45 %) developed preeclampsia, which resulted in preterm delivery, and 3 of the 12 pregnancies (25 %) achieved term delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those without (45 % [5/11] vs. 15 % [11/74]; p<0.05, and 73 % [8/11] vs. 34 % [25/74]; p<0.05, respectively). Among women with pain, the maximum C-reactive protein level was significantly higher in women who developed preeclampsia than in those who did not (5.45 vs. 0.12 mg/dL, p<0.05)., Conclusions: Our study revealed that adenomyosis can cause pain in over one of eight pregnancies with adenomyosis, which may be associated with the increased incidence of preeclampsia resulting in preterm delivery. Women with pain, especially those with high C-reactive protein levels, may be at high risk for future development of preeclampsia and consequent preterm delivery., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Cervical intraepithelial neoplasia (CIN) diagnosis is based on colposcopy-aided histological examination. However, its accuracy in CIN diagnosis is limited. Some invasive cervical cancers (ICCs) are diagnosed after cervical conization. Therefore, risk stratification of undetected ICC is particularly important for the management of patients with CIN. This study aimed to identify the risk factors for undetected ICC. We especially focused on the association of human papillomavirus (HPV) genotypes., Methods: We retrospectively reviewed the clinicopathological characteristics (including age, parity, and preoperative diagnosis) and HPV genotypes of 348 patients diagnosed with CIN or adenocarcinoma in situ (AIS) who underwent cervical conization at our hospital between 2008 and 2016. The relationship between preoperative factors, including HPV genotypes and post-conization ICC, was evaluated., Results: Among the 348 patients, 322, 7, and 19 had preoperative CIN3, CIN2, and AIS, respectively; 181 were nulliparous. The median patient age was 41 (23-83) years. HPV genotyping was performed on 237 patients. Overall, post-conization ICC was detected in 16 patients (4.6%). Multivariate analysis showed that nulliparity and HPV16 positivity were the independent risk factors for post-conization ICC (OR: 6.01, P = 0.0302; OR: 5.26, P = 0.0347, respectively). The combination of HPV16 status and parity improved diagnostic accuracy. Seven of 53 HPV16-positive cases (13%) without childbirth history were diagnosed with post-conization ICC. In contrast, none of the HPV16-negative cases with childbirth history was diagnosed with post-conization ICC., Conclusion: HPV16 positivity and nulliparity were identified as risk factors for undetected ICC. Careful treatment selection and preoperative scrupulous examination are especially important in these cases., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: Although adenomyosis is reportedly associated with adverse pregnancy outcomes, clinical factors related to the high risk of obstetric complications are unclear. This study aimed to elucidate the characteristics of adenomyosis lesions associated with the increased incidence of obstetric complications based on imaging findings., Methods: This was a retrospective, observational cohort study conducted in a tertiary perinatal care center. Eighty-eight singleton pregnant women with adenomyosis were included in the study. Based on magnetic resonance imaging or ultrasonography before and/or during pregnancy, patients were classified according to three types of image characteristics: the extent of adenomyosis lesion (focal type or diffuse type), location of the lesion (extrinsic type, intrinsic type, or indeterminate type), the positional relationship between the lesion and the placenta (placenta distant from adenomyosis or placenta over adenomyosis), and the incidence of obstetric complications were examined., Results: Patients with diffuse type adenomyosis are significantly more likely to have spontaneous second-trimester miscarriage (diffuse type vs. focal type: 16.7 vs. 0%, p  < .01), preterm premature rupture of membranes (19.4 vs. 1.9%, p  < .01), and preeclampsia (25.0 vs. 7.7%, p  = .02), as compared to those with focal type adenomyosis. In a comparison of the three location types, the incidence of placental malposition was higher in patients with the extrinsic type adenomyosis (extrinsic type vs. intrinsic type vs. indeterminate type: 20.0 vs. 6.7 vs. 2.3%, p  = .03). Comparisons between the types of the placenta over or distant from adenomyosis lesion displayed no significant differences in the frequencies of obstetric complications., Conclusions: We demonstrated that the frequency of obstetric complications related to adenomyosis varies depending on the extent and location of the lesion; patients with diffuse type adenomyosis have an increased risk of spontaneous second-trimester miscarriage, preterm premature rupture of membranes, and preeclampsia, while patients with extrinsic type adenomyosis have an increased risk of placental malposition. Imaging evaluation of adenomyosis prior to conception or early in pregnancy may be useful for the obstetrical risk assessment among patients with adenomyosis.

The purpose of this study is to clarify the metabolic dependence of ovarian clear cell carcinoma (CCC) by comparing normal tissues and to examine the applicability of fluorescence imaging probe to exploit these metabolic differences. Enhanced glutathione synthesis was supported by the increased uptake of related metabolites and elevated expression levels of genes. Accumulation of intracellular iron and lipid peroxide, induction of cell death by inhibition of the glutathione synthesis pathway indicated that ferroptosis was induced. The activation of γ-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a fluorescent imaging probe that recognizes γ-glutamyl transferase, which is essential for the synthesis of glutathione, was investigated in fresh-frozen surgical specimens. gGlu-HMRG detected extremely strong fluorescent signals in the tumor lesions of CCC patients, compared to normal ovaries or endometrium. These results revealed that CCC occurs in the stressful and unique environment of free radical-rich endometrioma, and that glutathione metabolism is enhanced as an adaptation to oxidative stress. Furthermore, a modality that exploits these metabolic differences would be useful for distinguishing between CCC and normal tissues., (© 2023. The Author(s).)

Purpose: Although many patients with endometrial cancer (EC) or atypical endometrial hyperplasia (AEH) achieve complete remission (CR) after high-dose medroxyprogesterone acetate (MPA) treatment, no consensus has been reached on management after CR. Currently, patients receive estrogen-progestin maintenance therapy, but no recommendations exist regarding the duration of maintenance therapy or whether hysterectomy should be considered. This study aimed to provide insights into the management of EC/AEH after achieving CR., Methods: We retrospectively investigated the prognosis of 50 patients with EC or AEH who achieved CR after MPA therapy. We assessed the association between disease recurrence and clinicopathological features and the pre- and post-operative histological diagnoses of patients who underwent hysterectomy., Results: The median follow-up duration was 34 months (range: 1-179 months). Recurrence was observed in 17 patients. Among the clinical characteristics investigated, only the primary disease was significantly associated with disease recurrence; patients with EC had a higher risk of recurrence than those with AEH (p = 0.037). During the observation period, 27 patients attempted pregnancy, and 14 pregnancies resulted in delivery. Patients who gave birth had significantly longer relapse-free survivals than those who did not (p = 0.031). Further, 16 patients underwent hysterectomies, and AEH was detected postoperatively in 4 of 11 patients (36.4%) with no preoperative abnormalities., Conclusions: We identified several clinical features of patients with EC and AEH after CR. Given the high probability of endometrial abnormalities detected postoperatively, hysterectomy may be considered for patients who no longer want children., (© 2023. The Author(s).)

Background: Adenomyosis is associated with unfavorable perinatal outcomes; however, the effect of an adenomyomectomy on pregnancy outcomes remains unclear. Pregnancy following an adenomyomectomy has been reported to be associated with a high risk for uterine rupture; however, the actual incidence remains unknown., Objective: This study aimed to evaluate the effect of an adenomyomectomy on pregnancy outcomes by retrospectively comparing the pregnancy outcomes of women who underwent an adenomyomectomy with those of women with adenomyosis., Study Design: This was a single-center retrospective study in which the pregnancy outcomes of women who underwent an adenomyomectomy and for whom complete resection of the affected tissue under laparotomy was achieved were compared with those of women with adenomyosis. The following pregnancy outcomes were examined: second-trimester miscarriage, preterm prelabor rupture of membranes, preterm delivery, spontaneous preterm delivery, preeclampsia, rate of cesarean delivery, blood loss during cesarean delivery, incidence of placenta accreta spectrum, neonatal body weight, and small for gestational age infants., Results: A total of 18 pregnant women who underwent an adenomyomectomy and 105 pregnant women with adenomyosis were included in this study. All women who underwent an adenomyomectomy delivered via cesarean delivery, and among them, 1 had a uterine rupture at 30 weeks of gestation. Although there was no significant difference between pregnant women who underwent an adenomyomectomy and those with adenomyosis in the incidence of second-trimester miscarriage (0% [0/18] vs 7.6% [8/105], respectively; P =.22), preterm delivery (50% [9/18] vs 32% [34/105], respectively; P =.15), and spontaneous preterm delivery (6% [1/18] vs 15% [16/105], respectively; P =.26), a significant decrease in preterm prelabor rupture of membrane (0% [0/18] vs 12% [13/105], respectively; P <.05), preeclampsia (0% [0/18] vs 12% [13/105], respectively; P <.05), and small for gestational infants (0% [0/18] vs 15% [16/105], respectively; P <.05), as well as a significant increase in the incidence of placenta accreta spectrum (50% [9/18] vs 0% [0/105], respectively; P <.01) and blood loss during cesarean delivery (1748 mL vs 1330 mL, respectively; P <.05) were observed., Conclusion: Uterine rupture following an adenomyomectomy may occur because of the high incidence of placenta accreta spectrum. However, an adenomyomectomy may reduce adverse pregnancy outcomes associated with adenomyosis, such as preterm prelabor rupture of membranes, preeclampsia, and small for gestational age infants. An adenomyomectomy may be a viable option for women among whom the procedure is inevitable before conception., (© 2023 The Authors.)

Background: The efficacy of adjuvant therapy for patients with cervical cancer with intermediate risk (CC-IR) remains controversial. We examined the impact of adjuvant therapy on survival outcomes in patients with CC-IR and evaluated the heterogeneous treatment effects (HTEs) of adjuvant therapies based on clinicopathologic characteristics., Methods: We retrospectively analyzed a previous Japanese nationwide cohort of 6192 patients with stage IB-IIB cervical cancer who underwent radical hysterectomy. We created two pairs of propensity score-matched treatment/control groups to investigate the treatment effects of adjuvant therapies: (1) adjuvant therapy versus non-adjuvant therapy; (2) chemotherapy versus radiotherapy conditional on adjuvant therapy. Multivariate analyses with treatment interactions were performed to evaluate the HTEs., Results: Among the 1613 patients with CC-IR, 619 and 994 were in the non-treatment and treatment groups, respectively. Survival outcomes did not differ between the two groups: 3-year progression-free survival (PFS) rates were 88.1% and 90.3% in the non-treatment and treatment groups, respectively (p = 0.199). Of the patients in the treatment group, 654 and 340 received radiotherapy and chemotherapy, respectively. Patients who received chemotherapy had better PFS than those who received radiotherapy (3-year PFS, 90.9% vs. 82.9%, p = 0.010). Tumor size was a significant factor that affected the treatment effects of chemotherapy; patients with large tumors gained better therapeutic effects from chemotherapy than those with small tumors., Conclusion: Adjuvant therapy is optional for some patients with CC-IR; however, chemotherapy can be recommended as adjuvant therapy, particularly for patients with large tumors., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Single-agent chemotherapy with or without bevacizumab (Bev) is a standard therapy for platinum-resistant ovarian cancer (PR-OC). However, there is a lack of literature on chemotherapy agent selection in heterogenous PR-OC. Therefore, we aimed to clarify the heterogeneous treatment effects of each chemotherapy agent., Methods: Patients who underwent single-drug chemotherapy agents or Bev combination therapy for PR-OC between January 2009 and June 2022 were included in this study. We assessed the impact of each chemotherapy agent on the time to treatment failure (TTF) according to histological type, platinum-free interval (PFI), and Bev usage., Results: A total of 158 patients received 343 different chemotherapy regimens. In patients with clear cell carcinoma/mucinous carcinoma (CC/MC), gemcitabine (GEM) had the strongest effect with a median TTF of 5.3 months, whilst nedaplatin (NDP) had the lowest effect with a median TTF of 1.4 months. In contrast, in the non-CC/MC group, irinotecan (CPT-11) and NDP had a better TTF than GEM and pegylated liposomal doxorubicin (PLD). There were notable differences in the treatment efficacy of NDP according to PFI. Specifically, NDP prolonged the TTF in patients with a PFI ≥ 3 months. Compared with GEM alone, GEM + Bev tended to prolong the TTF more effectively; however, an additive effect was not observed with PLD + Bev., Conclusions: This study demonstrated that the effect of chemotherapy agents differed according to the tumor and background characteristics of the patient. Our findings will improve selection of effective therapies for patients with PR-OC by considering their background characteristics., (© 2023. The Author(s).)

Background: Left ventricular (LV) pseudo-false aneurysm is a rare and fatal complication secondary to myocardial infarction. Sometimes, it may perforate the right ventricle (RV) and lead to acute heart failure. We experienced 2 cases of surgical repair of an LV pseudo-false aneurysm perforating the RV., Case Presentation: Case 1: A 76-year-old man was referred to our hospital due to dyspnea. Echocardiography revealed an LV pseudo-false aneurysm (25 mm × 20 mm) that had perforated the RV. Via LV incision, the two small orifices communicating to the RV were detected and closed by direct suture. A double patch of bovine pericardium and a dacron sheet was sutured around the aneurysm with everting mattress. Case 2: A 51-year-old man, who had undergone percutaneous coronary intervention 1 month before, was referred to our hospital due to an LV aneurysm perforating the RV. Via LV incision, a double-layered patch was sutured around the aneurysm with everting mattress. The communicating hole to RV was closed by bovine pericardium patch with a running suture via an RV incision. Postoperative course was uneventful in both cases., Conclusions: An LV pseudo-false aneurysm perforating the RV should be considered for urgent repair before serious complications arise and the patient's general condition deteriorates., (© 2023. The Author(s).)

Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. Although it is estimated that HPV-associated cervical cancer will decrease with the widespread use of HPV vaccine, it may take time for HPV-associated cervical cancer to be eliminated. For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. First, the cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix. Therefore, it is important to understand the characteristics of SCJ for cervical cancer screening and treatment. Second, cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). Third, in addition to the type of HPV, the involvement of the human immune response is also important in the progression and regression of cervical cancer. In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer., (© 2023. The Author(s).)

Glucose is essential as the main energy source for living organisms. However, excessive elevation of blood sugar levels can lead to diabetes and serious complications such as arteriosclerosis. Even though blood sugar levels as well as hypoxia associated with hyperglycemia are known to be closely related to diabetes complications, the responses of vascular endothelial cells to glucose and oxygen have not been fully investigated. In this study, using a microfluidic device that can control the oxygen concentration, we observed the behavior of vascular endothelial cell monolayers while simultaneously controlling glucose and oxygen levels. Results showed that the cell migration speed was increased by high-glucose exposure in an oxygen-rich environment, but was decreased in a hypoxic environment regardless of glucose condition. The expression of vascular endothelial-cadherin at the cell periphery, which plays a role in cell-cell adhesion, was increased by hypoxic exposure, but was largely independent of glucose condition. This suggested that cell-cell adhesion is less involved in the increase in migration caused by high glucose. Furthermore, stabilization and nuclear translocation of hypoxia-inducible factor-1α, which is involved in cellular hypoxia sensing, increased 5 h after exposure to high glucose, but decreased 3 days after the exposure. This indicated that intracellular hypoxia was generated by increased oxygen consumption in mitochondria just after the high-glucose exposure, but it was moderated within 3 days.

Recently, artificial intelligence (AI) has been applied in various fields due to the development of new learning methods, such as deep learning, and the marked progress in computational processing speed. AI is also being applied in the medical field for medical image recognition and omics analysis of genomes and other data. Recently, AI applications for videos of minimally invasive surgeries have also advanced, and studies on such applications are increasing. In the present review, studies that focused on the following topics were selected: i) Organ and anatomy identification, ii) instrument identification, iii) procedure and surgical phase recognition, iv) surgery-time prediction, v) identification of an appropriate incision line, and vi) surgical education. The development of autonomous surgical robots is also progressing, with the Smart Tissue Autonomous Robot (STAR) and RAVEN systems being the most reported developments. STAR, in particular, is currently being used in laparoscopic imaging to recognize the surgical site from laparoscopic images and is in the process of establishing an automated suturing system, albeit in animal experiments. The present review examined the possibility of fully autonomous surgical robots in the future., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Sone et al.)

Purpose: Pegylated liposomal doxorubicin (PLD)-induced hand-foot syndrome (HFS) frequently lowers the quality of life of ovarian cancer patients. Wrist and ankle cooling, having a limited preventive effect, has been the commonest supportive HFS care. In this study, we retrospectively assessed the primary preventive effect of a combination of regional cooling and oral dexamethasone therapy (cooling + oral Dex) on HFS., Methods: This study is a single-arm retrospective, observational study. Recurrent ovarian cancer patients were administered PLD ± bevacizumab. We retrospectively examined the efficacy of hands and feet cooling (from the start of PLD to the end) + oral Dex (day 1-5: 8 mg/day, day 6, 7: 4 mg/day) for primary HFS prevention., Results: This study included 74 patients. The initial dose of PLD was 50 mg/m 2 and 40 mg/m 2 for 32 (43.2%) and 42 (56.8%) patients, respectively. HFS of Grade ≥ 2 and Grade ≥ 3 developed in five (6.8%) and one (1.4%) patient(s), respectively. The incidence of ≥ Grade 2 and ≥ Grade 3 HFS was much lower than those reported in previous studies. Dose reduction was required in 13 patients (17.6%) mainly because of neutropenia or mucositis; there was no HFS-induced dose reduction. Meanwhile, PLD therapy was discontinued mainly because of interstitial pneumonia (4 patients) and HFS (one patient)., Conclusions: We demonstrated the efficacy of regional cooling and oral Dex for primary prevention of PLD-induced HFS. Although future prospective studies are needed to confirm its efficacy, this combination therapy can be considered for primary prevention of HFS in ovarian cancer patients on PLD., (© 2023. The Author(s).)

Vascular endothelial cells (ECs) respond to mechanical stimuli caused by blood flow to maintain vascular homeostasis. Although the oxygen level in vascular microenvironment is lower than the atmospheric one, the cellular dynamics of ECs under hypoxic and flow exposure are not fully understood. Here, we describe a microfluidic platform for the reproduction hypoxic vascular microenvironments. Simultaneous application of hypoxic stress and fluid shear stress to the cultured cells was achieved by integrating a microfluidic device and a flow channel that adjusted the initial oxygen concentration in a cell culture medium. An EC monolayer was then formed on the media channel in the device, and the ECs were observed after exposure to hypoxic and flow conditions. The migration velocity of the ECs immediately increased after flow exposure, especially in the direction opposite to the flow direction, and gradually decreased, resulting in the lowest value under the hypoxic and flow exposure condition. The ECs after 6-h simultaneous exposure to hypoxic stress and fluid shear stress were generally aligned and elongated in the flow direction, with enhanced VE-cadherin expression and actin filament assembly. Thus, the developed microfluidic platform is useful for investigating the dynamics of ECs in vascular microenvironments., (© 2023. The Author(s).)

Background: Small cell carcinoma of the uterine cervix (SCCC) is a rare and highly malignant human papillomavirus (HPV)-associated cancer in which human genes related to the integration site can serve as a target for precision medicine. The aim of our study was to establish a workflow for precision medicine of HPV-associated cancer using patient-derived organoid., Methods: Organoid was established from the biopsy of a patient diagnosed with HPV18-positive SCCC. Therapeutic targets were identified by whole exome sequencing (WES) and RNA-seq analysis. Drug sensitivity testing was performed using organoids and organoid-derived mouse xenograft model., Results: WES revealed that both the original tumor and organoid had 19 somatic variants in common, including the KRAS p.G12D pathogenic variant. Meanwhile, RNA-seq revealed that HPV18 was integrated into chromosome 8 at 8q24.21 with increased expression of the proto-oncogene MYC. Drug sensitivity testing revealed that a KRAS pathway inhibitor exerted strong anti-cancer effects on the SCCC organoid compared to a MYC inhibitor, which were also confirmed in the xenograft model., Conclusion: In this study, we confirmed two strategies for identifying therapeutic targets of HPV-derived SCCC, WES for identifying pathogenic variants and RNA sequencing for identifying HPV integration sites. Organoid culture is an effective tool for unveiling the oncogenic process of rare tumors and can be a breakthrough for the development of precision medicine for patients with HPV-positive SCCC., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A 77-year-old man presented with a 1-month history of cough, pharyngeal discomfort, and weight loss. Chest radiography revealed a mass shadow in the right upper lung field. Bronchoscopy showed multiple white nodules along the tracheal cartilage ring. Although adenocarcinoma cells were detected in the mass, several biopsy specimens of the tracheal lesions exhibited no malignancy. 18 F-fluorodeoxyglucose positron emission tomography revealed an intense accumulation in the mass, nasal septum, and tracheal cartilage. Furthermore, anti-type II collagen antibody levels were elevated. We finally diagnosed him with lung cancer complicated by relapsing polychondritis. Treatment with oral prednisolone was initiated, followed by sequential chemoradiotherapy for lung cancer.

The cellular origins of cervical cancer and the histological differentiation of human papillomavirus (HPV)-infected cells remain unexplained. To gain new insights into the carcinogenesis and histological differentiation of HPV-associated cervical cancer, we focused on cervical cancer with mixed histological types. We conducted genomic and transcriptomic analyses of cervical cancers with mixed histological types. The commonality of the cellular origins of these cancers was inferred using phylogenetic analysis and by assessing the HPV integration sites. Carcinogenesis was estimated by analyzing human gene expression profiles in different histological types. Among 42 cervical cancers with known HPV types, mixed histological types were detected in four cases, and three of them were HPV18-positive. Phylogenetic analysis of these three cases revealed that the different histological types had a common cell of origin. Moreover, the HPV-derived transcriptome and HPV integration sites were common among different histological types, suggesting that HPV integration could occur before differentiation into each histological type. Human gene expression profiles indicated that HPV18-positive cancer retained immunologically cold components with stem cell properties. Mixed cervical cancer has a common cellular origin among different histological types, and progenitor cells with stem-like properties may be associated with the development of HPV18-positive cervical cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The effects of post-operative adjuvant radiotherapy (RT) on intermediate-risk patients with cervical cancer have not been fully elucidated. Therefore, the present study aimed to investigate the impact of RT on intermediate-risk cervical cancer. The data of 112 patients with stage IB and IIA cervical cancer treated with radical hysterectomy between January 2009 and December 2018 were retrospectively reviewed. Overall survival (OS), progression-free survival (PFS), and the frequency of adverse events were compared between patients with and without adjuvant RT (RT + and RT - , respectively). Subgroup analyses of PFS based on tumor size, cervical stromal invasion, lymphovascular space invasion and histology [squamous cell carcinoma (SCC) vs. non-SCC] were performed. Among the 112 patients, 41 received adjuvant RT. Although there were no significant differences in OS or PFS between the RT + and RT - groups, the frequency of adverse events was much higher in the RT + group. Patients in the RT + group also had more recurrent risk factors than those in the RT - group. Based on the subgroup analyses, although no significant differences were observed between any of the groups, RT demonstrated a different impact on PFS between SCC and non-SCC: No difference was observed in the SCC group, whereas patients in the RT + group tended to have poorer prognoses compared to those in the RT - group of the non-SCC group. These results suggest that the impact of post-operative RT on stage IB and IIA cervical cancer is limited and is accompanied by increased adverse events. The eligibility of patients for post-operative RT should be carefully determined based on the therapeutic effect of RT in each subgroup., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Ishizawa et al.)

Background: No previous study has evaluated the transitions of intrapartum transperineal ultrasound parameters during labor progression in cephalic malposition., Objective: We aimed to quantitate the characteristic trends of fetal head position and descent in cephalic malposition by analyzing the transitions of intrapartum transperineal ultrasound parameters and explore an indicator associated with the degree of cephalic malposition., Study Design: We retrospectively analyzed pregnant women who delivered at term from January 2018 to December 2020 at the University of Tokyo Hospital. The fetal occipital position was classified as occiput anterior and nonocciput anterior according to the fetal occipital angle of 0° to 75° and 75° to 180°, respectively. Fetal occipital angle was defined by the midline angle and position of the ocular orbit. The differences in the trends of head direction, head-symphysis distance, and progression distance relative to the angle of progression between occiput anterior and nonocciput anterior cases were evaluated. In addition, the parameters that showed differences were analyzed to evaluate their relationship to the degree of cephalic malposition., Results: A total of 502 images (occiput anterior, 319; nonocciput anterior, 183) met the inclusion criteria. The distribution of head direction values relative to the angle of progression was smaller in the nonocciput anterior group than in the occiput anterior group, whereas the head-symphysis distance and progression distance values relative to the angle of progression showed no difference in their distribution between the occiput anterior and nonocciput anterior groups. The ratio of head direction to the angle of progression was significantly smaller in the nonocciput anterior group than in the occiput anterior group (median [interquartile range], 0.03 [-0.02 to 0.10] vs 0.21 [0.12-0.28]; P<.0001). Furthermore, this ratio was negatively correlated with fetal occipital angle (Spearman correlation coefficient, -0.66)., Conclusion: Our results indicated that the head direction to angle of progression ratio reflects the deviation in the fetal head direction toward the maternal dorsal side, and decreases in proportion to the degree of cephalic malposition. This concept of deviation in the head direction as an indicator for evaluating cephalic malposition with intrapartum transperineal ultrasound may contribute to improving labor management in the case of cephalic malposition., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Preeclampsia (PE) is a hypertensive obstetric disorder with poor prognosis for both the mother and offspring. Infants born to mothers with PE are known to be at increased risk of developing higher brain dysfunction, such as autism. However, how maternal PE can affect the environment in the fetal brain has not been fully elucidated. Here, we examined the impact of PE on the fetal brain in a mouse model of PE induced by angiotensin II (Ang II), focusing on changes in the inflammatory condition. We confirmed that pregnant mice which were continuously administered Ang II exhibited PE phenotypes, including high blood pressure, proteinuria, and fetal growth restriction. Quantitative RT-PCR analysis demonstrated that the brain of fetuses on embryonic day 17.5 (E17.5) in the Ang II-administered pregnant mice showed increased expression of cytokines, interleukin (IL)- 6, IL-17a, tumor necrosis factor-α, interferon-γ, IL-12, IL-4, and IL-10. Immunohistochemical analysis over a wide area, from the tip of the frontal lobe to the posterior cerebral end, on E17.5 revealed that the microglia in the fetal brain of the Ang II-administered group displayed higher solidity and circularity than those of the control group, indicating that the microglia had transformed to an amoeboid morphology and were activated. Our findings suggest that maternal PE may cause altered inflammatory conditions in the fetal brain, which might be associated with the pathological mechanism connecting maternal PE and brain dysfunction in the offspring., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)