Transcription factor Ikzf1 associates with Foxp3 to repress gene expression in Treg cells and limit autoimmunity and anti-tumor immunity.

The master transcription factor of regulatory T (Treg) cells, forkhead box protein P3 (Foxp3), controls Treg cell function by targeting certain genes for activation or repression, but the specific mechanisms by which it mediates this activation or repression under different conditions remain unclear. We found that Ikzf1 associates with Foxp3 via its exon 5 (IkE5) and that IkE5-deficient Treg cells highly expressed genes that would otherwise be repressed by Foxp3 upon T cell receptor stimulation, including Ifng. Treg-specific IkE5-deletion caused interferon-γ (IFN-γ) overproduction, which destabilized Foxp3 expression and impaired Treg suppressive function, leading to systemic autoimmune disease and strong anti-tumor immunity. Pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3-Ikzf1-Ikzf3 complex competed with epigenetic co-activators, such as p300, for binding to target gene loci via chromatin remodeling. Therefore, the Ikzf1 association with Foxp3 is essential for the gene-repressive function of Foxp3 and could be exploited to treat autoimmune disease and cancer.

Fatal SARS-CoV-2 Infection among Children, Japan, January-September 20221.

To determine the characteristics of pediatric patients 0-19 years of age who died after onset of SARS-CoV-2 infection in Japan during January 1-September 30, 2022, we reviewed multiple sources. We identified 62 cases, collected detailed information from medical records and death certificates, and conducted interviews, resulting in 53 patients with detailed information for our study. Among 46 patients with internal causes of death (i.e., not external causes such as trauma), 15% were <1 year of age, 59% had no underlying disease, and 88% eligible for vaccination were unvaccinated. Nonrespiratory symptoms were more common than respiratory symptoms. Out-of-hospital cardiac arrest affected 46% of patients, and time from symptom onset to death was <7 days for 77%. Main suspected causes of death were central nervous system abnormalities (35%) and cardiac abnormalities (20%). We recommend careful follow-up of pediatric patients after SARS-CoV-2 infection during the first week after symptom onset, regardless of underlying diseases.

CD25+FOXP3+CD45RA- regulatory T-cell infiltration as a prognostic biomarker for endometrial carcinoma.

BACKGROUND: Regulatory T (Treg) cells reportedly play crucial roles in tumor angiogenesis as well as antitumor immunity. In order to explore their therapeutic potential, we investigated the precise prognostic impact of Treg markers in endometrial carcinoma. METHODS: We performed multiplexed immunofluorescence and quantitative image analyses of CD25, FOXP3, CTLA4, and CD45RA in tumor specimens from 176 consecutive patients treated at our institution for primary endometrial carcinomas. Bioinformatics analyses were further conducted to corroborate the findings. RESULTS: High CD25+, FOXP3+, and CD25+FOXP3+CD45RA- stromal cell counts correlated with better overall survival (OS) (p = 0.00019, 0.028 and 0.0012) and MSI-high (p = 0.015, 0.016 and 0.047). High CD45RA+ stromal cell count was associated with superficial myometrial invasion (p = 0.0038). Bioinformatics survival analysis by Kaplan-Meier plotter showed that high CD25, FOXP3, CTLA4, and CD45RA mRNA expressions correlated with better OS (p = 0.046, 0.00042, 0.000044, and 0.0022). Univariate and multivariate analyses with various clinicopathologic prognostic factors indicated that high CD25+ or CD25+FOXP3+CD45RA- stromal cell count was significant and independent for favorable OS (p = 0.0053 and 0.0015). We subsequently analyzed the correlations between the multiplexed immunofluorescence results and treatment-free interval (TFI) after primary chemotherapy in recurrent cases, finding no significant associations. Further analysis revealed that high ratio of CD25+ : CD8+ cell count or CD25+FOXP3+CD45RA- : CD8+ cell count correlated with longer TFI (p = 0.021 and 0.021). CONCLUSION: The current observations suggest that the balance between CD25+ or CD25+FOXP3+CD45RA- cells and CD8+ cells, corresponding to promoting or inhibiting effect on tumor angiogenesis, affect tumor chemosensitivity leading to prognostic significance. CD25+FOXP3+CD45RA- effector Treg tumor infiltration may serve as a useful prognostic biomarker and a potential target for immunotherapeutic manipulation of tumor chemosensitivity by novel management for advanced/recurrent endometrial carcinomas.

Formation of chalcogen-bonding interactions and their role in the trans-trans conformation of thiourea.

The chalcogen-bonding interactions formed at both sides of the thiocarbonyl group in thiourea were investigated. In particular, the role of these chalcogen-bonding interactions in the trans-trans conformation of thiourea was evaluated via single-crystal X-ray diffraction analysis and DFT calculations. The obtained results indicate that the Se⋯S⋯Se dual chalcogen-bonding interactions play a stronger role in controlling the planar structure than the S⋯S⋯S interactions.

Palladium-catalyzed C-C bond cleavage of N-cyclopropyl acylhydrazones.

Despite their utility as directing groups, the C-C bond cleavage of cyclopropanes utilizing hydrazones has not been explored. Herein, Pd-catalyzed C-C bond cleavage reaction of N-cyclopropyl acylhydrazones, followed by cycloisomerization to yield pyrazoles, has been developed. The protocol enables the synthesis of various α-pyrazole carbonyl compounds, which have a potential of biological activity. Control experiments and DFT calculations suggest that ß-carbon elimination of a stable 6-membered chelate palladium complex occurs, generating a conjugated azine as a reaction intermediate for the following cycloisomerization.

Potential prognostic predictors of treatment with immune checkpoint inhibitors for advanced endometrial cancer.

BACKGROUND: Prognostic predictors of immunotherapy in patients with advanced endometrial cancer remain unclear. The potential role of inflammatory predictors, including pretreatment neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and hemoglobin, albumin, lymphocyte and platelet scores, was investigated. METHODS: Between August 2018 and December 2023, 35 patients were retrospectively analyzed. Prognostic predictors were compared, and optimal cut-off values that exhibited the greatest discrimination for overall response, disease control, progression-free survival and overall survival were determined. Multivariate analysis was used to assess the prognostic significance of the predictors. RESULTS: The greatest discrimination for overall response, progression-free survival and overall survival included platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and hemoglobin, albumin, lymphocyte and platelet; the areas under the curve were 0.638, 0.649 and 0.641, respectively. The precise cut-off values of neutrophil-to-lymphocyte ratio for progression-free survival and overall survival were 4.92 and 5.40, respectively. The lower neutrophil-to-lymphocyte ratio group had a significantly longer progression-free survival (P = 0.001, median survival; 4.0 months vs. 19 months) and longer overall survival (P = 0.002, median survival; 5.0 months vs. 21 months). Of the risk factors assessed, neutrophil-to-lymphocyte ratio (hazard ratio = 4.409; 95% CI = 1.10-17.64; P = 0.036) and regimen (hazard ratio = 5.559; 95% CI = 1.26-24.49; P = 0.023) were independently correlated with overall survival. CONCLUSION: In patients with advanced endometrial cancer, pretreatment neutrophil-to-lymphocyte ratio may be a prognostic predictor of those who would benefit from immunotherapy.

A randomized phase II study of secondary cytoreductive surgery in patients with relapsed ovarian cancer who have progressed on a PARP inhibitor as first-line maintenance therapy: the SOCCER-P study (KGOG 3067/JGOG 3036/APGOT-OV11).

BACKGROUND: Although two recent phase III randomized controlled trials showed survival benefits of undergoing secondary cytoreductive surgery for an initial relapse of ovarian cancer, patients who received a poly-ADP ribose polymerase inhibitor (PARPi) as the first-line maintenance treatment, which is currently the standard treatment for advanced ovarian cancer, were not included in those trials. Therefore, determining an optimal treatment strategy, including secondary cytoreductive surgery, in patients whose cancer progresses even with PARPi treatment, is needed. PRIMARY OBJECTIVE: To determine whether secondary cytoreductive surgery is beneficial in patients who have progressed on PARPi maintenance treatment. STUDY HYPOTHESIS: Secondary cytoreductive surgery followed by chemotherapy is superior to chemotherapy alone for patients who have progressed on PARPi maintenance treatment. TRIAL DESIGN: The SOCCER-P study is a multicenter randomized phase II clinical trial. Patients who meet the eligibility criteria will be randomized to either undergo secondary cytoreductive surgery and subsequent platinum-based chemotherapy plus or minus bevacizumab, or to receive platinum-based chemotherapy plus or minus bevacizumab alone. Patients randomly allocated to the surgery group will undergo secondary cytoreductive surgery followed by six cycles of a physician's choice of platinum-based chemotherapy once they have recovered from surgery. MAJOR INCLUSION/EXCLUSION CRITERIA: The major inclusion criteria are as follows: first recurrence of disease with treatment-free interval from last platinum dose (TFIp) ≥6 months and progression during PARPi maintenance or treatment-free interval from last PARPi therapy (TFIPARPi) <3 months. The major exclusion criteria are as follows: >1 line of prior chemotherapy, TFIp <6 months, and radiological signs suggesting metastases not accessible to surgical removal (complete resection is deemed not possible). PRIMARY ENDPOINT: Progression-free survival. SAMPLE SIZE: 124 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual completion approximately the end of 2026 and the results are expected after 2 years of follow-up in 2029. TRIAL REGISTRATION: NCT05704621.

Favorable changes in the eGFR slope after dapagliflozin treatment and its association with the initial dip.

BACKGROUND: Renoprotective effects of sodium glucose transporter 2 (SGLT2) inhibitors, including dapagliflozin, were observed in randomized controlled trials (RCTs). The suspected underlying mechanism is a correction of hyperfiltration, observed as an "initial dip". Whether SGLT2 inhibitors can attenuate the rate of decline in the estimated glomerular filtration rate (eGFR) in clinical settings, even when considering the pre-treatment decline rate, is unknown. Although several RCTs identified an association between the initial dip and long-term renal prognoses, a conclusion has not been reached. METHODS: We collected the eGFR data of patients for whom dapagliflozin was initiated in our hospital and then calculated their eGFR slopes before and after the start of the treatment. We investigated the changes in the eGFR slopes (ΔeGFR slope) and the association between the ΔeGFR slope and the initial dip. Risks for rapid eGFR decliners (eGFR slope < - 3 mL/min/1.73 m2/year) were also examined. RESULTS: The eGFR slope was significantly milder after dapagliflozin treatment (p < 0.01). A deeper initial dip was associated with a milder rate of eGFR decline (adjusted beta: - 0.29, p < 0.001). Dapagliflozin treatment reduced the proportion of rapid eGFR decliners from 52.9 to 14.7%, and a smaller initial dip was identified as a significant risk for post-treatment rapid eGFR decline (adjusted odds ratio: 1.73, p < 0.05). CONCLUSIONS: Compared to before the administration of dapagliflozin, the rate of eGFR decline was significantly milder after its administration. The initial dip was significantly associated with long-term renoprotective effects and may be a useful predictor of treatment response.

HBD1 protein with a tandem repeat of two HMG-box domains is a DNA clip to organize chloroplast nucleoids in Chlamydomonas reinhardtii.

Compaction of bulky DNA is a universal issue for all DNA-based life forms. Chloroplast nucleoids (chloroplast DNA-protein complexes) are critical for chloroplast DNA maintenance and transcription, thereby supporting photosynthesis, but their detailed structure remains enigmatic. Our proteomic analysis of chloroplast nucleoids of the green alga Chlamydomonas reinhardtii identified a protein (HBD1) with a tandem repeat of two DNA-binding high mobility group box (HMG-box) domains, which is structurally similar to major mitochondrial nucleoid proteins transcription factor A, mitochondrial (TFAM), and ARS binding factor 2 protein (Abf2p). Disruption of the HBD1 gene by CRISPR-Cas9-mediated genome editing resulted in the scattering of chloroplast nucleoids. This phenotype was complemented when intact HBD1 was reintroduced, whereas a truncated HBD1 with a single HMG-box domain failed to complement the phenotype. Furthermore, ectopic expression of HBD1 in the mitochondria of yeast Δabf2 mutant successfully complemented the defects, suggesting functional similarity between HBD1 and Abf2p. Furthermore, in vitro assays of HBD1, including the electrophoretic mobility shift assay and DNA origami/atomic force microscopy, showed that HBD1 is capable of introducing U-turns and cross-strand bridges, indicating that proteins with two HMG-box domains would function as DNA clips to compact DNA in both chloroplast and mitochondrial nucleoids.

Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization.

A concise synthetic strategy utilizing a Zr-catalyst for the construction of cyctetryptomycin A and B is herein reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers via a Zr-catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr-catalyst required dppe as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

En bloc resection and reconstruction using a talar prosthesis for malignant talar bone tumor: a surgical technique.

En bloc resection is required for treatment of intermediate-grade talar tumors with extraosseous extension (Enneking stage 3) and malignant talar tumors without intra-articular invasion (Enneking stages IA and IIA). After resection, reconstruction options include tibiocalcaneal fusion, frozen autograft, and talar prosthesis; however, a talar prosthesis is preferable because it preserves ankle range of motion, does not cause leg length discrepancy, and is associated with good long-term outcomes. To the best of our knowledge, en bloc resection and reconstruction of a malignant talar tumor has not been previously reported in detail. We report a detailed surgical technique for en bloc resection of a malignant talar bone tumor using combined anterior and lateral approaches followed by reconstruction using a talar prosthesis.

Dual Chalcogen-Bonding Interactions for the Conformational Control of Urea.

Dual chalcogen-bonding interactions is proposed as a novel means for the conformational control of urea derivatives. The formation of a chalcogen-bonding interaction at both sides of the urea carbonyl group was unambiguously confirmed by X-ray diffraction as well as computational studies including non-covalent interaction (NCI) plot index analysis, quantum theory of atoms in molecules (QTAIM) analysis, and natural bond orbital (NBO) analysis via DFT calculations. By virtue of this dual interaction, urea derivatives that bear chalcogen atoms (X=S and Se) adopt a planar structure via the carbonyl oxygen (O) with an X⋅⋅⋅O⋅⋅⋅X arrangement on the same side of the molecule. The rigidity of the conformational lock was evaluated using the molecular arrangement in the crystal and the rotational barrier of benzochalcogenophene ring, which indicated a stronger conformational lock in benzoselenophene than in benzothiophene urea derivatives. Furthermore, the acidity of the urea derivatives increases according to the Lewis-acidic properties of the chalcogen-bonding interactions, whereby benzoselenophene urea is more acidic than benzothiophene urea. Tweezer-shaped urea derivatives were prepared, and their stereostructure proved the viability of the conformational control for defining the location of the substituents on the urea framework.

Cigarette smoke induces mitochondrial DNA damage and activates cGAS-STING pathway: application to a biomarker for atherosclerosis.

Cigarette smoking is a major risk factor for atherosclerosis. We previously reported that DNA damage was accumulated in atherosclerotic plaque, and was increased in human mononuclear cells by smoking. As vascular endothelial cells are known to modulate inflammation, we investigated the mechanism by which smoking activates innate immunity in endothelial cells focusing on DNA damage. Furthermore, we sought to characterize the plasma level of cell-free DNA (cfDNA), a result of mitochondrial and/or genomic DNA damage, as a biomarker for atherosclerosis. Cigarette smoke extract (CSE) increased DNA damage in the nucleus and mitochondria in human endothelial cells. Mitochondrial damage induced minority mitochondrial outer membrane permeabilization, which was insufficient for cell death but instead led to nuclear DNA damage. DNA fragments, derived from the nucleus and mitochondria, were accumulated in the cytosol, and caused a persistent increase in IL-6 mRNA expression via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. cfDNA, quantified with quantitative PCR in culture medium was increased by CSE. Consistent with in vitro results, plasma mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (n-cfDNA) were increased in young healthy smokers compared with age-matched nonsmokers. Additionally, both mt-cfDNA and n-cfDNA were significantly increased in patients with atherosclerosis compared with the normal controls. Our multivariate analysis revealed that only mt-cfDNA predicted the risk of atherosclerosis. In conclusion, accumulated cytosolic DNA caused by cigarette smoke and the resultant activation of the cGAS-STING pathway may be a mechanism of atherosclerosis development. The plasma level of mt-cfDNA, possibly as a result of DNA damage, may be a useful biomarker for atherosclerosis.

Oxidative Deprotection of Benzyl Protecting Groups for Alcohols by an Electronically Tuned Nitroxyl-Radical Catalyst.

The oxidative deprotection of benzyl (Bn) groups using nitroxyl-radical catalyst 1 and co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA) is reported. This catalyst is highly active for the oxidation of benzylic ethers because of the electronic tuning on account of the electron-withdrawing ester groups next to the catalytically active center. This catalytic system promotes deprotections at ambient temperature and has a broad substrate scope, including substrates possessing hydrogenation-sensitive functional groups, while the deprotection hardly proceeds when using well-known nitroxyl-radical catalysts such as 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO). The 1/PIFA system also promotes the deprotection of several benzylic protecting groups, including 2-naphthylmethyl (NAP) and 4-methylbenzyl (MBn) groups. Catalyst 1 was also effective for the direct synthesis of ketones and aldehydes from Bn ethers via deprotected alcohols using an excess of the co-oxidant PIFA.

The implication of calf circumference and grip strength in osteoporosis and bone mineral density among hemodialysis patients.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD), nutritional status, and uremia management have been emphasized for bone management in hemodialysis patients. Nevertheless, valuable data on the importance of muscle mass in bone management are limited, including whether conventional management alone can prevent osteoporosis. Thus, the importance of muscle mass and strength, independent of the conventional management in osteoporosis prevention among hemodialysis patients, was evaluated. METHODS: Patients with a history of hemodialysis 6 months or longer were selected. We assessed the risk for osteoporosis associated with calf circumference or grip strength using multivariable adjustment for indices of CKD-MBD, nutrition, and dialysis adequacy. Moreover, the associations between bone mineral density (BMD), calf circumference, grip strength, and bone metabolic markers were also evaluated. RESULTS: A total of 136 patients were included. The odds ratios (95% confidence interval) for osteoporosis at the femoral neck were 1.25 (1.04-1.54, P < 0.05) and 1.08 (1.00-1.18, P < 0.05) per 1 cm shorter calf circumference or 1 kg weaker grip strength, respectively. Shorter calf circumference was significantly associated with a lower BMD at the femoral neck and lumbar spine (P < 0.001). Weaker grip strength was also associated with lower BMD at the femoral neck (P < 0.01). Calf circumference or grip strength was negatively correlated with bone metabolic marker values. CONCLUSION: Shorter calf circumference or weaker grip strength was associated with osteoporosis risk and lower BMD among hemodialysis patients, independent of the conventional therapies.

Novel Capped-Needle Device: A Novel Safety Feature to Eliminate Air Bubbles in Hemodialysis.

INTRODUCTION: Air bubbles in the dialysis circuit are rarely visible after automatic priming; however, they are often visible after the needles are manually connected to the circuit. To prevent this issue, we thought to prime needles with a circuit at automatic priming by the hemodialysis machine. In order to achieve this idea, we designed and manufactured a novel capped needle to connect the needles to the extracorporeal circuit before the automatic priming of the hemodialysis machine. This study investigated the effectiveness of this novel capped needle and compared it with the conventional method for preventing air bubble contamination. METHODS: We tested novel capped needles ten times to evaluate whether the dialysis machine works appropriately and removes air bubbles even with the attached capped needle. Next, we performed 25 trials using the conventional method, in which skilled nurses manually connect the needle. In both methods, we thoroughly counted the air bubbles with our naked eyes. We predicted that the capped needle would leave few bubbles in the circuit. In order to evaluate fewer bubbles, we conducted an additional experiment using a microparticle counter to measure the size and number of the bubbles. RESULTS: We thoroughly searched for air bubbles during each of the ten tests but could not find any bubbles visible to the naked eye. In the conventional method, bubbles were visible in 29 out of 50 cases. The bubble count was significantly lower in the capped-needle method than in the conventional method (p < 0.0001, Pearson's χ2 test). In the additional experiments using the microparticle counter, the average remaining air volume in the extracorporeal circuit was 0.0999 ± 0.2438 nL when the priming was performed using the novel capped needles. CONCLUSION: The novel capped needle eliminated all visible bubbles efficiently and effectively; therefore, it could be a valuable device for hemodialysis treatment. The reduction of air from the dialysis circuit may improve patient prognosis.

Chapter 2:indications and dosing of anticancer drug therapy in patients with impaired kidney function, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022.

This comprehensive review discusses the dosing strategies of cancer treatment drugs for patients with impaired kidney function, specifically those with chronic kidney disease (CKD), undergoing hemodialysis, and kidney transplant recipients. CKD patients often necessitate dose adjustments of chemotherapeutic agents, e.g., platinum preparations, pyrimidine fluoride antimetabolites, antifolate agents, molecularly targeted agents, and bone-modifying agents, to prevent drug accumulation and toxicity due to diminished renal clearance of the administered drugs and their metabolites. In hemodialysis patients, factors such as drug removal from hemodialysis and altered pharmacokinetics demand careful optimization of anticancer drug therapy, including dose adjustment and timing of administration. While free cisplatin is removed by hemodialysis, most of the tissue- and protein-bound cisplatin remains in the body and rebound cisplatin elevations are observed after hemodialysis. It is not recommended hemodialysis for drug removal, regardless of timing. Kidney transplant patients encounter unique challenges in cancer treatment, as maintaining the balance between reduction of immunosuppression, switching to mTOR inhibitors, and considering potential drug interactions with chemotherapeutic agents and immunosuppressants are crucial for preventing graft rejection and achieving optimal oncologic outcomes. The review underscores the importance of personalized, patient-centric approaches to anticancer drug therapy in patients with impaired kidney function.

Clinical availability and characteristics of multigene panel testing for recurrent/advanced gynecologic cancer.

BACKGROUND: Japan's health insurance covers multigene panel testing. This study aimed to determine the potential availability and utility of gene panel testing clinically in gynecologic oncology. METHODS: We analyzed the characteristics of patients with gynecologic cancer who underwent gene panel testing using FoundationOne® CDx or OncoGuide™ NCC Oncopanel between November 2019 and October 2022. RESULTS: Out of 102 patients analyzed, 32, 18, 43, 8, and 1 had cervical, endometrial, ovarian cancers, sarcoma, and vaginal cancer, respectively. Druggable gene alteration was found in 70 patients (68.6%; 21 with cervical cancer, 15 with endometrial cancer, 28 with ovarian cancer, 5 with sarcoma, and 1 with other). The most common druggable gene alteration was PIK3CA mutation (n = 21), followed by PTEN mutation (n = 12) and high tumor mutation burden (TMB-H) (n = 11). TMB-H was detected in 5 patients with cervical cancer, 5 with endometrial cancer, and 1 with endometrial stromal sarcoma. Eleven patients (10.8%) received molecularly targeted therapy according to their gene aberrations. Gene panel testing was mostly performed when the second-line treatment was ineffective. Of all 102 patients, 60 did not have recommended treatment, and 15 died or had worsened conditions before obtaining the test results. CONCLUSION: Through multigene panel testing, although many patients had druggable gene alterations, 10.8% of them received the recommended treatment. TMB-H was mainly observed in cervical/endometrial cancer, suggesting its potential as a therapeutic biomarker of immune checkpoint inhibitors. Furthermore, patients' prognosis and performance status should be considered before performing the test.

Cytopathological features associated with POLE mutation in endometrial cancer.

OBJECTIVE: For patients with endometrial cancer, the POLE (polymerase epsilon) mutation (POLEmut)-subtype, one of four molecular-analysis-based categories in the Cancer Genome Atlas (TCGA), has the best prognosis. The following histological characteristics are typically observed in endometroid carcinoma cases with the POLEmut-subtype: (1) the presence of tumour giant cells, (2) numerous tumour-infiltrating lymphocytes (TILs) and/or peri-tumoral lymphocytes, and (3) a high grade. However, in the context of cytology, the morphological characteristics of this subtype remain unknown. METHODS: DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues was subjected to next-generation sequencing analysis and categorised according to the TCGA classifications. Genomic mutation, tumour mutation burden (TMB), and microsatellite instability were also assessed. Cytological specimens of resected uteri obtained using the Papanicolaou method were histologically separated into three types. RESULTS: Seven out of 112 patients (6%) with endometrial cancer were diagnosed with the POLEmut-subtype between January 2019 and August 2021. Tumour giant cells were observed in three cases (43%) on histology and cytology. TIL and/or peritumoral lymphocytes with inflammatory cells were detected in five cases (71%) on histology and three cases (43%) on cytology. Cases in which these three characteristics were observed on both cytology and histology may have belonged to the POLEmut-subtype. There were no cases in which these characteristics were absent on histology but present on cytology. TMB tended to be higher in cases when the three characteristics were observed in both cytological and histological findings. CONCLUSIONS: Preoperative endometrial cytology highlighted the characteristics of the POLEmut-subtype in the histological analysis of resected uterine specimens and has the potential to play an important role in treatment decisions.

Molecular biological analysis revealed a case of synchronous endometrial and ovarian cancer with different histological grade as metastatic ovarian cancer from endometrial cancer: Case report and review of literature.

The diagnosis of synchronous endometrial and ovarian cancer or metastatic cancer of the same histological type is difficult. In this study, molecular biology analysis was performed to determine ovarian metastasis from endometrial cancer. A 38-year-old woman had pathological evidence of endometrial cancer (endometrioid carcinoma, grade 1) and ovarian cancer (endometrioid carcinoma, grade 3); a disseminated nodule in the serosa uteri was also diagnosed as endometrioid carcinoma (grade 3). Customized panel sequencing revealed a common mutation pattern in ovarian cancer and disseminated nodules. Furthermore, endometrial cancer showed the same mutation patterns for FGFR3 and PTEN as ovarian cancer and disseminated nodules. All tumors were microsatellite instability high. Clinicopathological and molecular biology analyses suggested that the patient had ovarian metastasis from endometrial cancer. The patient underwent adjuvant chemotherapy with paclitaxel and carboplatin, with no recurrence. Molecular biology techniques may enable appropriate treatment based on clinically accurate diagnosis.