Publications by authors named "Daisuke Aoki"

460 Publications

Evaluation of the Role of Intraoperative Frozen Section and Magnetic Resonance Imaging in Endometrial Cancer.

Int J Gynaecol Obstet 2022 Aug 5. Epub 2022 Aug 5.

Department of Obstetrics and Gynecology, International University of Health and Welfare, School of Medicine, Chiba, Japan.

Objective: Histological type, grade, and myometrial invasion are major prognostic features of endometrial carcinoma since it can alter the decision-making on surgical procedure. This study aimed to evaluate the accuracy of preoperative endometrial biopsy and magnetic resonance imaging (MRI) of endometrial cancer compared to that of intraoperative frozen section.

Methods: This retrospective study included 264 patients who underwent surgery with intraoperative frozen section for endometrial cancer at our institution between 2014 and 2018. Diagnosis was determined by histological type, grade, and myometrial invasion. Concordance rate, sensitivity, and specificity of preoperative diagnosis and intraoperative frozen diagnosis were calculated, in comparison to the final pathological diagnosis.

Results: Preoperative and intraoperative diagnoses showed no statistically significant difference in determining histological type and grade (p=0.152). Intraoperative diagnosis showed higher sensitivity for endometrioid carcinoma grade-3 and other types, and higher specificity for grade-1. For myometrial invasion, intraoperative diagnosis showed significantly higher concordance rate than preoperative MRI findings (p<0.01). Intraoperative diagnosis showed higher sensitivity and specificity in patients with and without myometrial invasion, respectively.

Conclusion: Higher agreement between intraoperative and final diagnoses, especially in myometrial invasion, suggests that intraoperative frozen section is a good indicator for appropriate surgical procedure decision-making.
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http://dx.doi.org/10.1002/ijgo.14389DOI Listing
August 2022

Current Status of Hereditary Breast and Ovarian Cancer Practice Among Gynecologic Oncologists in Japan: A Nationwide Survey by the Japan Society of Gynecologic Oncology (JSGO).

J Gynecol Oncol 2022 Jul 18. Epub 2022 Jul 18.

Kumamoto University, Kumamoto, Japan.

Objective: The practices pertaining to hereditary breast and ovarian cancer (HBOC) in Japan have been rapidly changing owing to the clinical development of poly(ADP-ribose) polymerase inhibitors, the increasing availability of companion diagnostics, and the broadened insurance coverage of HBOC management from April 2020. A questionnaire of gynecologic oncologists was conducted to understand the current status and to promote the widespread standardization of future HBOC management.

Methods: A Google Form questionnaire was administered to the members of the Japan Society of Gynecologic Oncology. The survey consisted of 25 questions in 4 categories: respondent demographics, HBOC management experience, insurance coverage of HBOC management, and educational opportunities related to HBOC.

Results: A total of 666 valid responses were received. Regarding the prevalence of HBOC practice, the majority of physicians responded in the negative and required human resources, information sharing and educational opportunities, and expanded insurance coverage to adopt and improve HBOC practice. Most physicians were not satisfied with the educational opportunities provided so far, and further expansion was desired. They remarked on the psychological burdens of many HBOC managements. Physicians reported these burdens could be alleviated by securing sufficient time to engage in HBOC management, creating easy-to-understand explanatory material for patients, collaboration with specialists in genetic medicine, and educational opportunities.

Conclusion: Gynecologic oncologists in Japan are struggling to deal with psychological burdens in HBOC practice. To promote the clinical practice of HBOC management, there is an urgent need to strengthen human resources and improve educational opportunities, and expand insurance coverage for HBOC management.
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http://dx.doi.org/10.3802/jgo.2022.33.e61DOI Listing
July 2022

Efficacy and safety of olaparib maintenance monotherapy for Japanese patients with platinum-sensitive relapsed ovarian, fallopian tube, and primary peritoneal cancer.

Int J Clin Oncol 2022 Jul 15. Epub 2022 Jul 15.

Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: Olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer has been approved in Japan since April 2018. Here, we report the experience administering this therapy in our hospital, with the aim of evaluating efficacy and safety in the Japanese population.

Methods: The study included 52 patients with platinum-sensitive relapsed ovarian, fallopian tube, and primary peritoneal cancer. All patients started olaparib at a dose of 300 mg twice daily. Information about treatment efficacy and adverse effects was collected retrospectively from medical records.

Results: Median age was 58 years old (range: 33-80), and 82.7% of the patients were diagnosed with high-grade serous carcinoma. Sixteen patients (30.8%) possessed the BRCA1/2 pathogenic variant (15 germline and 1 tissue), 3 (5.8%) possessed variants of unknown significance (2 germline and 1 tissue), 16 (30.8%) possessed wild type, and 17 (32.7%) were not analyzed. Median progression-free survival was 15.3 months (95% CI 9.0-21.6). Patients with BRCA1/2 pathogenic variants showed significantly longer PFS than patients with wild-type BRCA1/2 (p = 0.007). Disease progression caused 34 cases to discontinue olaparib. Eighteen (34.6%) individuals exhibited ≥ grade 3 anemia, although they recovered in response to appropriate management. One patient discontinued olaparib because of prolonged renal dysfunction. Another patient presented with grade 3 fatigue, but recovered after 2 weeks of interruption and continued olaparib treatment.

Conclusion: Olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer in the Japanese population is sufficiently safe and no less effective than reports from previous studies.
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http://dx.doi.org/10.1007/s10147-022-02212-xDOI Listing
July 2022

Living donor surgery in uterus transplantation: A delicate hysterectomy technique in gynecological surgery.

J Obstet Gynaecol Res 2022 Jul 7. Epub 2022 Jul 7.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/jog.15355DOI Listing
July 2022

Incidence of fistula occurrence in patients with cervical cancer treated with bevacizumab: data from real-world clinical practice.

Int J Clin Oncol 2022 Jun 27. Epub 2022 Jun 27.

Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: This study aimed to determine the incidence of pelvic fistulas in cervical cancer patients treated with bevacizumab in Japanese clinical practice.

Methods: A post-marketing surveillance (PMS) study was conducted between June 2016 and February 2018 to survey physicians who treated advanced or recurrent cervical cancer patients with bevacizumab (according to the product label). The clinical/treatment status of patients with pelvic fistulas was assessed in an additional retrospective case series study.

Results: 142 patients were included in the PMS study (median age 51 years; 66.9% squamous cell carcinoma; 66.2% recurrent cervical cancer; 64.1% previous radiotherapy). Patients received a median of seven bevacizumab doses. Six patients, all of whom had a history of pelvic irradiation, developed seven fistulas (4.2%; 95% confidence interval, 1.56-8.96), and five patients had also undergone pelvic surgery. The case series study of the patients who developed fistulas indicated that three patients had high cumulative bladder and rectal doses of radiation, and two of them had undergone salvage re-irradiation for pelvic recurrence. The other three patients underwent both radical hysterectomy and adjuvant radiotherapy, but did not receive an excessive radiation dose to the bladder or rectum.

Conclusions: This study found that the upper limit of the 95% confidence interval for pelvic fistula incidence did not exceed the incidence reported in the GOG 240 study. To ensure an adequate benefit-risk assessment of bevacizumab in cervical cancer patients, a comprehensive evaluation of prior treatment is essential and the possibility of unexpected fistulas, even after careful evaluation, should be considered.
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http://dx.doi.org/10.1007/s10147-022-02196-8DOI Listing
June 2022

Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis.

J Gynecol Oncol 2022 May 16. Epub 2022 May 16.

Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan.

Objective: Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis.

Methods: We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists.

Results: High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61).

Conclusion: Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.
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http://dx.doi.org/10.3802/jgo.2022.33.e57DOI Listing
May 2022

Characteristics and clinicopathological features of patients with ovarian metastasis of endometrial cancer: a retrospective study.

J Obstet Gynaecol 2022 Jun 2:1-7. Epub 2022 Jun 2.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

There are no criteria for patient selection for ovarian-preserving surgery for endometrial cancer (EC). In this study, intraoperative findings of ovarian swelling (OvS) and the clinicopathological features of patients with EC with or without ovarian metastasis were analysed to identify risk factors for ovarian metastasis. Patients who underwent surgery for EC between 2012 and 2019 at our hospital were enrolled. In univariate analysis, all features were significantly higher in metastasis(+) cases. In multivariate analysis, lymphatic space invasion (LSI), cervical stromal involvement (CSI), peritoneal dissemination, and OvS were significant risk factors. In univariate analysis in stage I and II cases classified without adnexal pathological factors, type 2 histologic type, LSI, CSI, and OvS were significantly higher in metastasis(+) cases. LSI, CSI, and OvS were significant risk factors in multivariate analysis. Patients with type 1 histologic type EC without myometrial invasion ≥1/2, CSI and extrauterine lesions are appropriate for ovarian preservation. IMPACT STATEMENT The number of premenopausal patients with endometrial cancer (EC) is increasing. Bilateral oophorectomy for EC results in surgical primary ovarian insufficiency, and thus, surgery with ovarian preservation has been examined. However, there are few reports on risk factors for ovarian metastasis of EC and no established criteria for patient background or pathological factors to determine suitability for ovarian preservation surgery. In univariate analysis, all pathological findings suggestive of disease progression were more frequent in cases with ovarian metastases. In multivariate analysis, lymphatic space invasion (LSI), cervical stromal involvement (CSI), peritoneal dissemination, and ovarian swelling (OvS) were identified as significant risk factors for ovarian metastasis. In an analysis of stage I and II cases classified without adnexal pathological factors, type 2 histologic type, LSI, CSI, and OvS were significantly more common in cases with ovarian metastasis, and LSI, CSI, and OvS emerged as significant risk factors for ovarian metastasis in multivariate analysis. Patients with type 1 histologic type EC without depth of myometrial invasion ≥1/2, CSI, or extrauterine lesions may be appropriate cases for ovarian preservation.
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http://dx.doi.org/10.1080/01443615.2022.2071148DOI Listing
June 2022

Self-Strengthening of Cross-Linked Elastomers via the Use of Dynamic Covalent Macrocyclic Mechanophores.

ACS Macro Lett 2021 05 21;10(5):558-563. Epub 2021 Apr 21.

The creation of polymeric materials that self-strengthen in response to a mechanical force is an important objective in the field of polymer chemistry. Here, the mechanochemical strengthening of cross-linked elastomers using macrocyclic mechanophores that contain a dynamic covalent disulfide bond is reported. Cross-linked poly(hexyl methacrylate) (CPHMA) polymers with macrocyclic mechanophores inserted at the cross-linking points were synthesized via free radical polymerization. Tensile and swelling tests showed that the addition of the macrocyclic mechanophores to the CPHMA polymers successfully impart them with self-strengthening functionality following compression, without the need for any additives such as monomers and modifiers, or any other stimuli.
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http://dx.doi.org/10.1021/acsmacrolett.1c00124DOI Listing
May 2021

Visualization of the Necking Initiation and Propagation Processes during Uniaxial Tensile Deformation of Crystalline Polymer Films via the Generation of Fluorescent Radicals.

ACS Macro Lett 2021 May 3;10(5):623-627. Epub 2021 May 3.

Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan.

To visualize and simultaneously quantify the necking behavior of crystalline polymer films during uniaxial stretching, tetraarylsuccinonitrile (TASN) moieties were introduced into polymers at the center of the main chain. TASN can produce a relatively stable radical that emits yellow fluorescence in response to mechanical stress. During the uniaxial elongation test of the TASN-centered crystalline polymers, the yellow fluorescence derived from the dissociated TASN radicals was used for microscale observations that showed the orientation of the polymer chains in the stretching direction. Furthermore, by comparing the radical generation in linear and star-shaped TASN-centered crystalline polymers during their tensile deformation, we found that the TASN dissociation ratio is higher in the star-shaped polymer, which has more chains connected to the lamellar crystal. Thus, the microforces generated in the amorphous region during uniaxial stretching were probed via the use of TASN, which allowed a direct visualization of the necking initiation and propagation processes as well as a quantification via electron paramagnetic resonance spectroscopy.
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http://dx.doi.org/10.1021/acsmacrolett.1c00185DOI Listing
May 2021

variants in p53 signatures and the clonality of STICs in RRSO samples.

J Gynecol Oncol 2022 07 21;33(4):e50. Epub 2022 Mar 21.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Objective: Precursor lesions may be identified in fallopian tube tissue after risk-reducing salpingo-oophorectomy (RRSO) in patients with pathogenic variants of . Serous tubal intraepithelial carcinoma (STIC) is considered a precursor of high-grade serous carcinoma, whereas the significance of the p53 signature remains unclear. In this study, we investigated the relationship between the p53 signature and the risk of ovarian cancer.

Methods: We analyzed the clinicopathological findings and conducted DNA sequencing for variants of p53 signatures and STIC lesions isolated using laser capture microdissection in 13 patients with pathogenic variants of who underwent RRSO and 17 control patients with the benign gynecologic disease.

Results: pathogenic variants were detected significantly higher in RRSO group than control (p<0.001). No difference in the frequency of p53 signatures were observed between groups (53.8% vs 29.4%; p=0.17). sequencing and next-generation sequencing analysis in a patient with STIC and occult cancer revealed 2 mutations causing different p53 staining for STICs and another mutation shared between STIC and occult cancer.

Conclusion: The sequence analysis for revealed 2 types of p53 signatures, one with a risk of progression to STIC and ovarian cancer with pathological variants in and the other with a low risk of progression without pathological variants in as seen in control.
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http://dx.doi.org/10.3802/jgo.2022.33.e50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250861PMC
July 2022

Polystyrene Functionalized with Diarylacetonitrile for the Visualization of Mechanoradicals and Improved Thermal Stability.

ACS Macro Lett 2021 Jun 28;10(6):744-748. Epub 2021 May 28.

Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan.

The direct scission of polymer main chains leads to a decrease in the performance of the polymeric materials. Polystyrene-functionalized with diarylacetonitrile (DAAN) was prepared through a postpolymerization modification with 4-methoxymandelonitrile to generate mechanofluorescent polymers that enable the visualization of the scission of the polymer main chain. The polymeric mechanoradicals obtained from the homolytic cleavage of the polymer main chain in response to mechanical stress were observed using fluorescence and electron paramagnetic resonance spectroscopy. Moreover, a thermogravimetric analysis showed that the thermal stability of the polymers was greatly improved relative to the parent polystyrene, that is, the introduction of the DAAN moiety via postpolymerization modification endowed the original polymers with multiple functions in one step; specifically, the ability to visualize polymer main-chain scission and improved thermal stability.
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http://dx.doi.org/10.1021/acsmacrolett.1c00352DOI Listing
June 2021

Climacteric symptoms in postoperative patients among endometrial cancer, cervical cancer, and ovarian cancer: a cross-sectional study.

Support Care Cancer 2022 Aug 8;30(8):6785-6793. Epub 2022 May 8.

Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: To date, no studies have assessed climacteric symptoms after hystero-adnexectomy for endometrial, cervical, or ovarian cancer. Thus, this study aimed to compare climacteric symptoms among patients who underwent surgery for these three cancer types.

Methods: In this cross-sectional study, we interviewed patients who were registered at a menopausal outpatient clinic between January 1999 and July 2016 after undergoing total hysterectomy, intrapelvic only or intrapelvic plus para-aortic lymph node dissection, and bilateral adnexectomy performed via laparotomy as a cancer treatment. Climacteric symptoms were assessed using a patient-reported questionnaire covering core domains with five symptoms only at the initial consultation. Each symptom was graded from 0 (no symptoms) to 3 (severe symptoms). We evaluated the frequency of symptom severity according to the time elapsed since surgery and the cancer type.

Results: The numbers of patients with endometrial, ovarian, and cervical cancer were 328, 90, and 107, respectively. Overall, climacteric symptoms were more severe in patients with cervical cancer than in those with endometrial or ovarian cancer; symptom severity decreased with increasing time since surgery. However, symptom severity did not decrease significantly over time in patients with cervical cancer even after > 5 years had elapsed since surgery.

Conclusion: The climacteric symptoms were less severe in patients with endometrial or ovarian cancer with longer time elapsed since surgery but not in those with cervical cancer. Patients with cervical cancer may require more prompt interventions, including symptomatic treatment and longer follow-up period, than those with endometrial or ovarian cancer.
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http://dx.doi.org/10.1007/s00520-022-07117-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213383PMC
August 2022

Remarkable diastereomeric effect on thermoresponsive behavior of polyurethane based on lysine and tartrate ester derivatives.

RSC Adv 2021 Oct 3;11(56):35607-35613. Epub 2021 Nov 3.

Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology 8916-5 Takayama-cho Ikoma Nara 630-0192 Japan

This study describes the long-distance diastereomeric effect on thermoresponsive properties in water-soluble diastereomeric polyurethanes (PUs) composed of an l-lysine ethyl ester diisocyanate and a trimethylene glycol l-/d-tartrate ester, which have differences in spatial arrangements of the ethyl esters in the mirror image. The PUs based on l-lysine and l-/d-tartrate ester, named l-PU and d-PU, were synthesized with various number average molecular weights from 4700 to 13 100. In turbidimetry, l-PU showed a steep phase transition from 100% to 0% within about 10 °C at 4 g L, whereas d-PU did not change completely to 0% transmittance even at 80 °C at 4 g L. In addition, the thermoresponsive properties of l-PU were less affected by concentration than those of d-PU. This long-distance diastereomeric effect on thermoresponsive behavior between l-PU and d-PU appeared in common among 6 samples with 4700 to 13 100 number average molecular weight. In the dynamic light scattering experiments at each transmittance, the hydrodynamic diameter ( ) of l-PU increased up to 1000 nm, while the of d-PU remained almost at 200-300 nm. The C[double bond, length as m-dash]O stretching vibration of FT-IR spectra showed that d-PU has more hydrogen-bonded ester groups than L-PU. Thus, we speculated that the difference in the retention of polymer chains in the micelle to promote intermicellar bridging generates the long-distance diastereomeric effect.
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http://dx.doi.org/10.1039/d1ra05877kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043254PMC
October 2021

Considerations in performing hysterectomy secondary to uterus transplantation.

Acta Obstet Gynecol Scand 2022 Aug 20;101(8):933-934. Epub 2022 Apr 20.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/aogs.14368DOI Listing
August 2022

Mechanochromic elastomers with different thermo- and mechano-responsive radical-type mechanophores.

Soft Matter 2022 Apr 20;18(16):3218-3225. Epub 2022 Apr 20.

Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan.

To design tough soft materials, the introduction of sacrificial bonds into their skeleton is a useful method. The introduction of radical-type mechanophores (RMs), which generate coloured radicals in response to mechanical stimuli, as sacrificial bonds into the cross-linking points of elastomers is expected to be a powerful tool to elucidate the fracture mechanisms as well as the toughening of materials, given that the radicals generated from the RMs are coloured and can be quantitatively evaluated using electron paramagnetic resonance (EPR) measurements. In this study, to investigate the effect of the dynamic nature, , the reactivity, of RMs introduced at the cross-linking points of polymer networks on their macroscopic mechanical properties, polymer networks cross-linked by two different RMs, a symmetric radical-type mechanophore (DFSN) and a non-symmetric radical-type mechanophore (CF/ABF), were synthesized and characterized. Compared to the polymer network cross-linked by DFSN, the network with CF/ABF exhibited higher thermal and mechanical responses, in other words much more sensitive to heat and mechanical force, resulting in better stress relaxation and energy-dissipation properties. These results demonstrate that the reactivity of the radical mechanophore at the cross-linking point is an important factor for designing polymer networks.
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http://dx.doi.org/10.1039/d1sm01786aDOI Listing
April 2022

Efficient Softening and Toughening Strategies of Cellulose Nanofibril Nanocomposites Using Comb Polyurethane.

Biomacromolecules 2022 04 1;23(4):1693-1702. Epub 2022 Apr 1.

Department of Chemistry, A3BMS Lab-Active, Adaptive and Autonomous Bioinspired Material Systems, 55128 Mainz, Germany.

Cellulose nanofibrils (CNFs) have attracted attention as building blocks for sustainable materials owing to their high performance and the advantages of their abundant natural resources. Bioinspired CNF/polymer nanocomposites, consisting of a soft polymer phase and a high fraction (>50 wt %) of CNF reinforcement, have been focused on excellent mechanical properties, including Young's modulus, mechanical strength, and toughness, mimicking the energy dissipation system in nature. However, efficient softening and toughening with a small amount of the soft phase is still a challenge because a large amount of the polymer phase (nearly 50%) is still required to provide ductility and toughness. Here, we describe a topological strategy in the polymer phase for efficient toughening of bioinspired CNF nanocomposites with a water-soluble comb polyurethane (PU). The comb PU provided higher elongation at break and more efficient flexibility for the nanocomposite than the linear PU, even at a small content. Moreover, CNF nanocomposites with 30 wt % of PU content and tetrabutylammonium as bulky counterions showed enhanced toughness (180% higher) and strain at break (250% higher) when compared to pure CNF due to the promotion of slippage between nanofibrils. Scanning electron microscopy (SEM) images of the fracture surface for CNF/comb PU nanocomposites displayed the pull-out of mesoscale layers and nanofibrils, supporting that the comb topology promotes the slippage between fibrils. Furthermore, the rheological study revealed that the comb PU has an entanglement plateau modulus lower than linear PU by 1 order of magnitude, related to the loosened entanglements. Our study establishes an efficient softening and toughening strategy while using small amounts of polymer phase addition, promoting interfibrillar slippage with the loosely entangled comb PU phase.
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http://dx.doi.org/10.1021/acs.biomac.1c01625DOI Listing
April 2022

Adenocarcinoma or early-stage cervical cancer is a risk factor for preterm delivery after cervical conization: a multicenter observational study.

J Matern Fetal Neonatal Med 2022 Mar 27:1-6. Epub 2022 Mar 27.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Objective: Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery.

Methods: We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks).

Results: Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity ( = .014) was higher and a history of preterm delivery ( = .0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group ( = .0099 and .0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26-13.68,  = .019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88-46.42,  < .0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55-34.86,  = .012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24-20.73,  = .024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11-16.62,  = .035) increased the risk of preterm delivery in the multiple regression models in primiparous women.

Conclusion: Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGESPrior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization.The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.
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http://dx.doi.org/10.1080/14767058.2022.2056835DOI Listing
March 2022

Ancient Evolutionary History of Human Papillomavirus Type 16, 18 and 58 Variants Prevalent Exclusively in Japan.

Viruses 2022 02 24;14(3). Epub 2022 Feb 24.

Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.

Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type variants, have been described for HPV genomes, together with geographical differences in the distribution of genotypes and variants. Here, by employing a maximum likelihood method, we performed phylogenetic analyses of the complete genome sequences of HPV16, HPV18 and HPV58 available from GenBank ( = 627, 146 and 157, respectively). We found several characteristic clusters that exclusively contain HPV genomes from Japan: two for HPV16 (sublineages A4 and A5), one for HPV18 (sublineage A1) and two for HPV58 (sublineages A1 and A2). Bayesian phylogenetic analyses of concatenated viral gene sequences showed that divergence of the most recent common ancestor of these Japan-specific clades was estimated to have occurred ~98,000 years before present (YBP) for HPV16 A4, ~39,000 YBP for HPV16 A5, ~38,000 YBP for HPV18 A1, ~26,000 for HPV58 A1 and ~25,000 YBP for HPV58 A2. This estimated timeframe for the divergence of the Japan-specific clades suggests that the introduction of these HPV variants into the Japanese archipelago dates back to at least ~25,000 YBP and provides a scenario of virus co-migration with ancestral Japanese populations from continental Asia during the Upper Paleolithic period.
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http://dx.doi.org/10.3390/v14030464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8953638PMC
February 2022

Aurora kinase blockade drives de novo addiction of cervical squamous cell carcinoma to druggable EGFR signalling.

Oncogene 2022 04 7;41(16):2326-2339. Epub 2022 Mar 7.

Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan.

Oncogenic signalling confers tumour-progression advantages; thus, its pharmacological blockade is the best strategy for cancer chemotherapy. However, drug resistance and heterogeneous dependency of tumour hamper their therapeutic potential, suggesting the necessity for a new ubiquitous modality based on evading drug resistance. Here, we proposed a de novo addiction to oncogenic signalling (Dead-On) concept, wherein specific blockade of target molecules forces cancer cells to develop dependency on an oncogenic signalling. In cervical squamous cell carcinoma cells, Aurora A/B dual blockade elicited rapid addiction to EGFR-Erk signalling, and its pharmacological/genetic inhibition synergistically enhanced anti-cancer activities in vitro, in vivo, and in a patient-derived organoid model. The signal activation was independent of EGFR genetic status, it was triggered by receptor accumulation on the plasma membrane via Rab11-mediated endocytic recycling machinery. These findings support our novel Dead-On concept which may lead to drug discovery as well as expand the adaptation of approved targeted drugs.
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http://dx.doi.org/10.1038/s41388-022-02256-3DOI Listing
April 2022

Response Predictive Markers and Synergistic Agents for Drug Repositioning of Statins in Ovarian Cancer.

Pharmaceuticals (Basel) 2022 Jan 21;15(2). Epub 2022 Jan 21.

Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

In the field of drug repurposing, the use of statins for treating dyslipidemia is considered promising in ovarian cancer treatment based on epidemiological studies and basic research findings. Biomarkers should be established to identify patients who will respond to statin treatment to achieve clinical application. In the present study, we demonstrated that statins have a multifaceted mode of action in ovarian cancer and involve pathways other than protein prenylation. To identify biomarkers that predict the response to statins, we subjected ovarian cancer cells to microarray analysis and calculated Pearson's correlation coefficients between gene expression and cell survival after statin treatment. The results showed that and were positively and negatively correlated with the response to statins, respectively. Histoculture drug response assays revealed that statins were effective in clinical samples. We also confirmed the synergistic effects of statins with paclitaxel and panobinostat and determined that statins are hematologically safe to administer to statin-treated mice. Future clinical trials based on the expression of the biomarkers identified in this study for repurposing statins for ovarian cancer treatment are warranted.
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http://dx.doi.org/10.3390/ph15020124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8880614PMC
January 2022

Mechanochromic cyclodextrins.

Chem Commun (Camb) 2022 Mar 1;58(18):3067-3070. Epub 2022 Mar 1.

Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan.

Mechanochromic cyclodextrins (MCDs) that can generate blue radical species, which are exceptionally stable toward atmospheric oxygen and can thus be quantitatively characterized electron paramagnetic resonance (EPR) spectroscopy, were synthesized. MCDs have a defined structure that consists of a diarylbibenzofuranone skeleton mechanophore sandwiched between two CDs. Grinding tests and EPR measurements of the MCDs revealed their high mechanoresponsiveness, reflecting the inherent rigidity of the CDs and the formation of a supramolecular structure in the bulk.
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http://dx.doi.org/10.1039/d2cc00363eDOI Listing
March 2022

A jerk-based algorithm ACCEL for the accurate classification of sleep-wake states from arm acceleration.

iScience 2022 Feb 1;25(2):103727. Epub 2022 Jan 1.

Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

Arm acceleration data have been used to measure sleep-wake rhythmicity. Although several methods have been developed for the accurate classification of sleep-wake episodes, a method with both high sensitivity and specificity has not been fully established. In this study, we developed an algorithm, named ACceleration-based Classification and Estimation of Long-term sleep-wake cycles (ACCEL) that classifies sleep and wake episodes using only raw accelerometer data, without relying on device-specific functions. The algorithm uses a derivative of triaxial acceleration (jerk), which can reduce individual differences in the variability of acceleration data. Applying a machine learning algorithm to the jerk data achieved sleep-wake classification with a high sensitivity (>90%) and specificity (>80%). A jerk-based analysis also succeeded in recording periodic activities consistent with pulse waves. Therefore, the ACCEL algorithm will be a useful method for large-scale sleep measurement using simple accelerometers in real-world settings.
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http://dx.doi.org/10.1016/j.isci.2021.103727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784328PMC
February 2022

Keio Uterus Transplantation Research: From Basic Research toward Future Clinical Application.

Keio J Med 2022 Jun 19;71(2):33-43. Epub 2022 Jan 19.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Uterus transplantation (UTx) is now a potential option to allow women with uterine factor infertility to give birth. However, UTx is still at an experimental stage, and basic animal studies, including in non-human primates, are needed for the accumulation of data prior to clinical application. Considering that UTx may provide new hope to Japanese women, we launched UTx research in 2009 and have since accumulated a large archive of results in the UTx research field. Furthermore, we have carried out various activities aimed at the implementation of clinical applications of UTx in Japan while clarifying the ethical and social issues involved. Currently, the clinical application of UTx in Japan is just around the corner, and it is expected that UTx research will develop further in the future. Herein, we summarize our basic experiences using non-human primates and our activities with the goal of future clinical applications.
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http://dx.doi.org/10.2302/kjm.2021-0008-IRDOI Listing
June 2022

Star-Polymer-DNA Gels Showing Highly Predictable and Tunable Mechanical Responses.

Adv Mater 2022 Apr 16;34(13):e2108818. Epub 2022 Feb 16.

Faculty of Advanced Life Science, Hokkaido University, Sapporo, 001-0021, Japan.

Dynamically crosslinked gels are appealing materials for applications that require time-dependent mechanical responses. DNA duplexes are ideal crosslinkers for building such gels because of their excellent sequence addressability and flexible tunability in bond energy. However, the mechanical responses of most DNA gels are complicated and unpredictable. Here, a DNA gel with a highly homogeneous gel network and well predictable mechanical behaviors is demonstrated by using a pair of star-polymer-DNA precursors with presimulated DNA sequences showing the two-state transition. The melting curve analysis of the DNA gels reveals the good correspondence between the thermodynamic potentials of the DNA crosslinkers and the presimulated values by DNA calculators. Stress-relaxation tests and dissociation kinetics measurements show that the macroscopic relaxation time of the DNA gels is approximately equal to the lifetime of the DNA crosslinkers over 4 orders of magnitude from 0.1-2000 s. Furthermore, a series of durability tests find the DNA gels are hysteresis-less and self-healable after the applications of repeated temperature and mechanical stimuli. These results demonstrate the great potential of star-polymer-DNA precursors for building gels with predictable and tunable viscoelastic properties, suitable for applications such as stress-response extracellular matrices, injectable solids, and soft robotics.
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http://dx.doi.org/10.1002/adma.202108818DOI Listing
April 2022

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2.

Int J Clin Oncol 2022 Feb 13;27(2):281-300. Epub 2022 Jan 13.

Division of Transfusion, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.
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http://dx.doi.org/10.1007/s10147-021-02076-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8827301PMC
February 2022

Status of cervical cancer screening among adolescents and young adults (AYA) in Japan.

Int J Clin Oncol 2022 Mar 11;27(3):473-480. Epub 2022 Jan 11.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan.

Cervical cancer ranks high among the cancers that affect people in their 20s and 30s. Cervical cancer is characterized by the presence of precancerous lesions, which can be detected by cancer screenings; some precancerous lesions are amenable to treatment, which can halt the progression to invasive cancer. As a result, cervical cancer screening has been shown to reduce the incidence of invasive cancer and its mortality. On the other hand, many precancerous lesions do not progress to invasive cancer, but stagnate or disappear spontaneously. In Japan, there is a nationwide cytological screening program for residents, and the screening is performed every two years after the age of 20. There are also screening programs provided by the workplaces in Japan. According to the National Health Survey 2019, the checkup rates of any type of cervical cancer screenings are low: 15.1% for those aged 20-24, 36.6% for those aged 25-29, and 49.4% for those aged 30-34. Statistics are reported every year for the nationwide screening, and according to them, the positive screening rate is 2.1% for all ages, but 4.5% and 3.2% for those in their 20s and 30s, respectively. On the other hand, the percentage of people with positive test results who undergo follow-up examinations or confirmatory tests should be at least 90%, but it is 72.1% for all ages, 72.0% for those in their 30s, and even lower for those in their 20s, at 67.1%. Improving the rate of people getting screenings and subsequent examinations is a challenge even among the young.
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http://dx.doi.org/10.1007/s10147-021-02100-wDOI Listing
March 2022

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1.

Int J Clin Oncol 2022 Feb 1;27(2):265-280. Epub 2022 Jan 1.

Division of Transfusion, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).
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http://dx.doi.org/10.1007/s10147-021-02081-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8816532PMC
February 2022

Clinical Usefulness of Endometrial Cytology in Determining the Therapeutic Effect of Fertility Preserving Therapy.

Acta Cytol 2022 15;66(2):106-113. Epub 2021 Dec 15.

Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Japan.

Introduction: The significance of endometrial cytology in determining the therapeutic efficacy of medroxyprogesterone acetate (MPA) therapy is unclear. This study aimed to evaluate the clinical usefulness of endometrial cytology during MPA therapy.

Methods: Overall, 77 patients who underwent dilatation and curettage (D&C) to evaluate the therapeutic efficacy of MPA therapy at our hospital between January 2018 and December 2019 were retrospectively analyzed. The results of D&C, cytological evaluation, and other clinicopathological factors were analyzed based on the patients' medical records.

Results: The sensitivity and specificity of cytology were 61% and 92%, respectively, with D&C being the gold standard for diagnosis in 142 D&C/cytological examinations. Among patients with no residual disease on D&C, 5 (4%) had suspicious or positive cytology. Although MPA therapy was terminated in 3 of these patients, only 1 patient had early recurrence, and the frequency of recurrence was similar to that of patients who showed negative results in both D&C and cytology.

Discussion/conclusion: The sensitivity of endometrial cytology in determining the therapeutic effect of MPA therapy is low, and we confirmed that the omission of D&C is unacceptable. Our findings also suggested that the addition of cytological evaluation to D&C during MPA therapy had a low clinical significance.
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http://dx.doi.org/10.1159/000520701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985004PMC
March 2022

Endometrial cancer.

Nat Rev Dis Primers 2021 12 9;7(1):88. Epub 2021 Dec 9.

Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Although endometrial cancer management remains challenging, a deeper understanding of the genetic diversity as well as the drivers of the various pathogenic states of this disease has led to development of divergent management approaches in an effort to improve therapeutic precision in this complex malignancy. This comprehensive review provides an update on the epidemiology, pathophysiology, diagnosis and molecular classification, recent advancements in disease management, as well as important patient quality-of-life considerations and emerging developments in the rapidly evolving therapeutic landscape of endometrial cancers.
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http://dx.doi.org/10.1038/s41572-021-00324-8DOI Listing
December 2021
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