A thermally driven rotaxane-catenane interconversion with a dynamic bis(hindered amino) disulfide.

We have developed a versatile and simple synthetic method to produce a [3]catenane. Heating a rotaxane with bis(hindered amino) disulfide groups at both ends spontaneously and selectively produces the [3]catenane. The successful polymerization of the obtained [3]catenane provides a platform for the synthesis of various interlocking polymers.

Impact of COVID-19 on gynecological cancer incidence: a large cohort study in Japan.

BACKGROUND: The influence of the coronavirus disease 2019 (COVID-19) pandemic on the number of newly diagnosed gynecological cancers has not been extensively investigated in Japan. This study determined the impact of COVID-19 on the incidence of gynecological cancer. METHODS: Using the Japanese Society of Obstetricians and Gynecologic Oncology registry database, the distribution of the number of patients based on clinical staging or tumor-node-metastasis classifications before and during the COVID-19 pandemic was analyzed to compare the trends. The clinical staging classification of cervical cancer in Japan was based on the International Federation of Gynecology and Obstetrics (FIGO) 2008 from 2018 to 2020 and on the FIGO 2018 from 2021. Since FIGO-2018 classified N1 cases as stage IIIC, we focused on T classification without referencing the clinical staging (FIGO staging) of patients with cervical cancer in 2021. RESULTS: The number of patients with endometrial cancer and malignant ovarian tumors of all clinical stages increased uniformly yearly, while that of those with stage III cervical cancer rapidly increased in 2021 owing to the adoption of the revised classification. On comparing cases of cervical cancer in 2020 and 2021, we found that T1 cases decreased and T2 and T3 cases increased in 2021 compared to those in 2020 (p = 0.006). Cervical intraepithelial neoplasia/adenocarcinoma in situ incidence decreased in 2020 compared to that in 2019 but increased again in 2021. The number of patients with cervical cancer decreased in most prefectures in 2020. CONCLUSION: The incidence of locally advanced cervical cancer increased during the COVID-19 pandemic.

Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2.

In recent years, rapid advancement in gene/protein analysis technology has resulted in target molecule identification that may be useful in cancer treatment. Therefore, "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" was published in Japan in September 2021. These guidelines were established to align the clinical usefulness of external diagnostic products with the evaluation criteria of the Pharmaceuticals and Medical Devices Agency. The guidelines were scoped for each tumor, and a clinical questionnaire was developed based on a serious clinical problem. This guideline was based on a careful review of the evidence obtained through a literature search, and recommendations were identified following the recommended grades of the Medical Information Network Distribution Services (Minds). Therefore, this guideline can be a tool for cancer treatment in clinical practice. We have already reported the review portion of "Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition" as Part 1. Here, we present the English version of each part of the Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition.

Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial.

BACKGROUND: Concurrent chemoradiotherapy has been the standard of care for locally advanced cervical cancer for over 20 years; however, 30-40% of treated patients have recurrence or progression within 5 years. Immune checkpoint inhibition has improved outcomes for patients with PD-L1 positive metastatic or recurrent cervical cancer. We assessed the benefit of adding durvalumab, a PD-L1 antibody, with and following chemoradiotherapy for locally advanced cervical cancer. METHODS: The CALLA randomised, double-blind, phase 3 trial included 105 hospitals across 15 countries. Patients aged at least 18 years with previously untreated locally advanced cervical cancer (adenocarcinoma, squamous, or adenosquamous; International Federation of Gynaecology and Obstetrics [FIGO] 2009 stage IB2-IIB lymph node positive, stage ≥III any lymph node status) and WHO or Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) through an interactive web response system using a permuted block size of 4 to receive durvalumab (1500 mg intravenously once every 4 weeks) or placebo with and following chemoradiotherapy, for up to 24 cycles. Chemoradiotherapy included 45 Gy external beam radiotherapy at 5 fractions per week concurrent with intravenous cisplatin (40 mg/m2) or carboplatin (area under the concentration-time curve 2) once weekly for 5 weeks, followed by image-guided brachytherapy (high-dose rate, 27·5-30 Gy or low-dose/pulse-dose rate, 35-40 Gy). Randomisation was stratified by disease stage status (FIGO stage and node status) and geographical region. Chemoradiotherapy quality was continuously reviewed. The primary endpoint was progression-free survival, assessed by the investigator using Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03830866. FINDINGS: Between Feb 15, 2019, and Dec 10, 2020, 770 women were randomly assigned (385 to durvalumab and 385 to placebo; median age 49 years [IQR 41-57]). Median follow-up was 18·5 months (IQR 13·2-21·5) in the durvalumab group and 18·4 months (13·2-23·7) in the placebo group. At data cutoff, median progression-free survival had not been reached (95% CI not reached-not reached) for either group (HR 0·84; 95% CI 0·65-1·08; p=0·17); 12-month progression-free survival was 76·0% (71·3-80·0) with durvalumab and 73·3% (68·4-77·5) with placebo. The most frequently reported grade 3-4 adverse events in both groups were anaemia (76 [20%] of 385 in the durvalumab group vs 56 [15%] of 384 in the placebo group) and decreased white blood cells (39 [10%] vs 49 [13%]). Serious adverse events occurred for 106 (28%) patients who received durvalumab and 89 (23%) patients who received placebo. There were five treatment-related deaths in the durvalumab group (one case each of urinary tract infection, blood loss anaemia, and pulmonary embolism related to chemoradiotherapy only; one case of endocrine disorder related to durvalumab only; and one case of sepsis related to both durvalumab and chemoradiotherapy). There was one treatment-related death in the placebo group (pneumonia related to chemoradiotherapy). INTERPRETATION: Durvalumab concurrent with chemoradiotherapy was well tolerated in participants with locally advanced cervical cancer, however it did not significantly improve progression-free survival in a biomarker unselected, all-comers population. Concurrent durvalumab plus chemoradiotherapy warrants further exploration in patients with high tumoral PD-L1 expression. Rigorous monitoring ensured high chemoradiotherapy compliance with advanced technology and allowed patients to receive optimal care. FUNDING: AstraZeneca.

Sacrificial Mechanical Bond is as Effective as a Sacrificial Covalent Bond in Increasing Cross-Linked Polymer Toughness.

Sacrificial chemical bonds have been used effectively to increase the toughness of elastomers because such bonds dissociate at forces significantly below the fracture limit of the primary load-bearing bonds, thereby dissipating local stress. This approach owes much of its success to the ability to adjust the threshold force at which the sacrificial bonds fail at the desired rate, for example, by selecting either covalent or noncovalent sacrificial bonds. Here, we report experimental and computational evidence that a mechanical bond, responsible for the structural integrity of a rotaxane or a catenane, increases the elastomer's fracture strain, stress, and energy as much as a covalent bond of comparable mechanochemical dissociation kinetics. We synthesized and studied 6 polyacrylates cross-linked by either difluorenylsuccinonitrile (DFSN), which is an established sacrificial mechanochromic moiety; a [2]rotaxane, whose stopper allows its wheel to dethread on the same subsecond time scale as DFSN dissociates when either is under tensile force of 1.5-2 nN; a structurally homologous [2]rotaxane with a much bulkier stopper that is stable at force >5.5 nN; similarly stoppered [3]rotaxanes containing DFSN in their axles; and a control polymer with aliphatic nonsacrificial cross-links. Our data suggest that mechanochemical dethreading of a rotaxane without failure of any covalent bonds may be an important, hitherto unrecognized, contributor to the toughness of some rotaxane-cross-linked polymers and that sacrificial mechanical bonds provide a mechanism to control material fracture behavior independently of the mechanochemical response of the covalent networks, due to their distinct relationships between structure and mechanochemical reactivity.

Japanese nationwide observational multicenter study of tumor BRCA1/2 variant testing in advanced ovarian cancer.

The association between germline BRCA1 and BRCA2 pathogenic variants (mutations: gBRCAm) and ovarian cancer risk is well established. Germline testing alone cannot detect somatic BRCA1/2 pathogenic variants (sBRCAm), which is calculated based on the proportion of tumor BRCAm (tBRCAm) from tumor samples and gBRCAm. Homologous recombination deficiency (HRD) results mainly from genetic/epigenetic alterations in homologous recombination repair-related genes and can be evaluated by genomic instability status. In Japan, the prevalence of tBRCAm, sBRCAm, and HRD remains unclear. This multicenter, cross-sectional, observational study, CHaRacterIzing the croSs-secTional approach to invEstigate the prevaLence of tissue BRCA1/2 mutations in newLy diagnosEd advanced ovarian cancer patients (CHRISTELLE), evaluated the prevalence of tBRCAm, sBRCAm, and HRD in tumor specimens from newly diagnosed patients with ovarian cancer who underwent gBRCA testing. Of the 205 patients analyzed, 26.8% had a tBRCAm, including tBRCA1m (17.6%) and tBRCA2m (9.3%). The overall prevalence of tBRCAm, gBRCAm, sBRCAm, and HRD-positive status was 26.8%, 21.5%, 6.3%, and 60.0%, respectively. The calculated sBRCAm/tBRCAm ratio was 23.6% (13/55), and the prevalence of gBRCA variant of uncertain significance was 3.9%. These results suggest gBRCA testing alone cannot clearly identify the best course of treatment, highlighting the importance of sBRCA testing in Japan. The present results also suggest that testing for tBRCA and HRD should be encouraged in advanced ovarian cancer patients to drive precision medicine.

Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma.

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

Theoretical and Experimental Investigations of Stable Arylfluorene-Based Radical-Type Mechanophores.

Invited for the cover of this issue are the groups of Hideyuki Otsuka at the Tokyo Institute of Technology and Koichiro Mikami at the Sagami Chemical Research Institute. The image depicts theoretical and experimental investigations of stable arylfluorene-based radical-type mechanophores. Read the full text of the article at 10.1002/chem.202203249.

Theoretical and Experimental Investigations of Stable Arylfluorene-Based Radical-Type Mechanophores.

Radical-type mechanophores (RMs) can undergo homolytic cleavage of their central C-C bonds upon exposure to mechanical forces, which affords radical species. Understanding the characteristics of these radical species allows bespoke mechanoresponsive materials to be designed and developed. The thermal stability of the central C-C bonds and the oxygen tolerance of the generated radical species are crucial characteristics that determine the functions and applicability of such RM-containing mechanoresponsive materials. In this paper, we report the synthesis and characterization of two series of arylfluorene-based RM derivatives, that is, 9,9'-bis(5-methyl-2-pyridyl)-9,9'-bifluorene (BPyF) and 9,9'-bis(4,6-diphenyl-2-triazyl)-9,9'-bifluorene (BTAF). BPyF and BTAF derivatives were synthesized without generating any peroxides initially, albeit that BPyF slowly converted to the corresponding peroxide in solution. DFT calculations revealed the importance of the thermodynamic stability and the values of the α-SOMO levels of the corresponding radical species for their thermal stability and oxygen tolerance. Furthermore, the mechanochromism of BTAF was demonstrated by ball-milling a BTAF-centered polymer, which was synthesized by atom-transfer radical polymerization (ATRP).

JGOG2046: a feasibility study of neoadjuvant chemotherapy followed by debulking surgery for clinically diagnosed FIGO stage IVb endometrial cancer.

BACKGROUND: We evaluated the feasibility of neoadjuvant chemotherapy, followed by debulking surgery, for clinically diagnosed FIGO stage IVb endometrial cancer (protocol number: JGOG2046). METHODS: The experimental treatment consisted of 3 cycles of paclitaxel (180 mg/m2) plus carboplatin (AUC5) followed by debulking surgery, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, and 3 cycles of adjuvant chemotherapy. Patients were considered as eligible if they were pathologically diagnosed as primary endometrial cancer, and had both endometrial tumor and distant metastasis confirmed by imaging examinations. The primary endpoint was the incidence of patients who completed debulking surgery after the neoadjuvant chemotherapy. RESULTS: While 51 patients were enrolled from 23 hospitals, the final study cohort consisted of 49 patients with a mean age of 59.0 years. Although the response ratio of the neoadjuvant chemotherapy was 65.3% (95% CI 50.4-78.3%), 67.3% (95% confidence interval (CI) 52.5-80.1%) underwent debulking surgery after the neoadjuvant chemotherapy and 59.2% (95% CI 45.2-71.8%) completed the protocol treatment including 3 courses of adjuvant chemotherapy. The median disease-free survival time was 9.1 months (95% CI 6.5-11.9), while the median overall survival time was 23.2 months (95% CI 11.9-27.8). A patient with sigmoid colon cancer and another with cervical cancer were included in this study. CONCLUSIONS: Neoadjuvant chemotherapy followed by debulking surgery was a feasible and acceptable treatment for metastatic endometrial cancer. (225 words).

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.

Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial.

BACKGROUND: The phase 3 VELIA trial evaluated veliparib with carboplatin/paclitaxel and as maintenance in patients with high-grade serous ovarian carcinoma. METHODS: Patients with previously untreated stage III-IV high-grade serous ovarian carcinoma were randomized 1:1:1 to control (placebo with carboplatin/paclitaxel and placebo maintenance), veliparib-combination-only (veliparib with carboplatin/paclitaxel and placebo maintenance), or veliparib-throughout (veliparib with carboplatin/paclitaxel and veliparib maintenance). Randomization stratification factors included geographic region (Japan versus North America or rest of the world). Primary end point was investigator-assessed median progression-free survival. Efficacy, safety, and pharmacokinetics were evaluated in a subgroup of Japanese patients. RESULTS: Seventy-eight Japanese patients were randomized to control (n = 23), veliparib-combination-only (n = 30), and veliparib-throughout (n = 25) arms. In the Japanese subgroup, median progression-free survival for veliparib-throughout versus control was 27.4 and 19.1 months (hazard ratio, 0.46; 95% confidence interval, 0.18-1.16; p = 0.1 [not significant]). In the veliparib-throughout arm, grade 3/4 leukopenia, neutropenia, and thrombocytopenia rates were higher for Japanese (32%/88%/32%) versus non-Japanese (17%/56%/28%) patients. Grade 3/4 anemia rates were higher in non-Japanese (65%) versus Japanese (48%) patients. Early introduction of olanzapine during veliparib monotherapy maintenance phase may help prevent premature discontinuation of veliparib, via its potent antiemetic efficacy. CONCLUSIONS: Median progression-free survival was numerically longer in Japanese patients in the veliparib-throughout versus control arm, consistent with results in the overall study population. Pharmacokinetics were comparable between Japanese and non-Japanese patients. Data for the subgroup of Japanese patients were not powered to show statistical significance but to guide further investigation.

Impact of the COVID-19 pandemic on surgery for benign diseases in gynecology: A nationwide survey by the Japan Society of Obstetrics and Gynecology.

AIM: This study aimed to clarify the impact of coronavirus disease 2019 on gynecology practice in Japan, in particular, on surgeries for benign gynecological diseases. METHODS: An online questionnaire was distributed to 966 facilities in Japan, including core facilities, facilities participating in perinatal and gynecologic oncology registries, and facilities certified for training by the Japanese Society of Obstetrics and Gynecology Endoscopy. The number of surgeries performed was compared between 2019 and 2020, when the novel coronavirus disease was prevalent. RESULTS: Five hundred and eighty (58.2%) facilities responded. The total number of surgeries decreased from 129 648 in 2019 to 118 565 in 2020, by 8.5%, for all surgical procedures. However, there was a clear increase in the number of robotic surgeries performed in 2020 compared to that in 2019 for all populations. The number of total hysterectomies decreased markedly from 15 385 in 2019 to 12 531 in 2020, a fall of 10.1%. CONCLUSIONS: The number of surgeries for benign gynecological diseases decreased by 8.5% in 2020 compared to that in 2019. This value is among the lowest in the world.

Study of the effects of in-person attendance at academic conferences on the health of the attendees under COVID-19 pandemic.

OBJECTIVE: To analyze the effects of in-person attendance at an academic conference held during the Covid-19 pandemic on the health of the attendees, as assessed based on symptoms such as fever and cough attributed to infection with the Covid-19 virus. METHODS: A questionnaire was used to survey the members of the Japan Society of Obstetrics and Gynecology (JSOG) about their health during the period from August 7 to August 12, 2022, after the 74th Annual Congress of the JSOG, which was held August 5 to 7. RESULTS: Our survey yielded responses from 3054 members (1566 of whom had attended the congress in person and 1488 of whom had not attended in person); 102 (6.5%) of the in-person attendees and 93 (6.2%) of the people who did not attend in person reported problems with their health. No statistically significant difference was found between these two groups (p = 0.766). In a univariate analysis of factors affecting the presence of health problems, attendees with age ≥60 years had significantly fewer health problems than attendees who were in their 20s (odds ratio: 0.366 [0.167-0.802; p = 0.0120]). In a multivariate analysis, attendees who had received four vaccine shots had significantly fewer health problems than attendees who had received three shots (odds ratio: 0.397 [0.229-0.690, p = 0.0010]). CONCLUSION: Congress attendees who took precautions at the congress to avoid being infected and who had a high vaccination rate did not develop significantly more health problems associated with in-person attendance at the congress.

Looking beyond carboplatin and paclitaxel for the treatment of advanced/recurrent endometrial cancer.

Endometrial cancer incidence and mortality are rising among all ethnic groups. Carboplatin plus paclitaxel is the established frontline treatment for advanced/recurrent disease; however, subsequent treatment with traditional cytotoxic chemotherapy is challenging. The molecular characterization of endometrial cancer has provided important insights into the biological drivers of carcinogenesis, which has allowed for the development of newer precision immunotherapies and targeted therapies, including pembrolizumab, dostarlimab, and lenvatinib. Until recently, platinum rechallenge was often considered at the time of recurrence, given the lack of other available therapeutic options; however, "platinum sensitivity" in endometrial cancer is subjective and largely based on expert opinion and/or practitioner experience. Small retrospective studies have tried to provide guidance on the utility of platinum rechallenge, but they are limited by variable patient characteristics and small sample sizes. The applicability of these retrospective studies to contemporary clinical practice is difficult in the setting of changing patient demographics, a better understanding of endometrial cancer drivers, and the recent approvals of immune checkpoint inhibitors and the combination of lenvatinib plus pembrolizumab in the second-line setting. The primary focus of this review is to distill the available data regarding platinum-doublet chemotherapy rechallenge and highlight recent pivotal developments in endometrial cancer treatment, as well as future directions.

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

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.

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

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, i.e., 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.

Clinical and pathological analysis of companion diagnostic testing of microsatellite instability-high for pembrolizumab in gynaecologic malignancy.

BACKGROUND: Microsatellite instability-high is a known biomarker for anti-PD-1/PD-L1 immune checkpoint therapy. It is also a known tumour feature of Lynch syndrome, detected most frequently in endometrial cancer. However, it remains unclear how microsatellite instability testing is carried out in the clinical field. METHODS: Ninety-nine patients with gynaecological malignant tumours who underwent microsatellite instability testing as a companion diagnosis for pembrolizumab and 16 patients who previously underwent microsatellite instability testing as a screening for Lynch syndrome were recruited. Clinical information, microsatellite instability status, outcomes, genetic assessments and information about cancer tissue were retrospectively analysed. RESULTS: Ninety-nine patients had 101 gynaecologic malignant tumours including 26 endometrial, 38 ovarian and 28 cervical cancers, 9 with other tumours including 2 synchronous endometrial and ovarian cancers. All tissue samples were successfully tested, even though some were ≥10-year-old samples. Three cases (3.0%, 3/99) showed microsatellite instability-high; all cases were endometrial cancers with one case of synchronous endometrial and ovarian cancer [11.5% (3/26) in endometrial cancer, 2.6% (1/38) in ovarian cancer], and there was no microsatellite instability-high in cervical and other cancers. One of the endometrial cancer patients received pembrolizumab treatment, but finally died of cancer. Two other cases underwent genetic testing; both were diagnosed as Lynch syndrome. Six cases (37.5%) showed microsatellite instability-high in screening for Lynch syndrome. CONCLUSIONS: Microsatellite instability-high was less commonly detected as a companion diagnosis for pembrolizumab in unselected gynaecologic patients. Genetic counselling should be always provided along with treatment selection.

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

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.

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