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Four subtypes of ovarian high-grade serous carcinoma (HGSC) have previously been identified, each with different prognoses and drug sensitivities. However, the accuracy of classification depended on the assessor's experience. This study aimed to develop a universal algorithm for HGSC-subtype classification using deep learning techniques. An artificial intelligence (AI)-based classification algorithm, which replicates the consensus diagnosis of pathologists, was formulated to analyze the morphological patterns and tumor-infiltrating lymphocyte counts for each tile extracted from whole slide images of ovarian HGSC available in The Cancer Genome Atlas (TCGA) data set. The accuracy of the algorithm was determined using the validation set from the Japanese Gynecologic Oncology Group 3022A1 (JGOG3022A1) and Kindai and Kyoto University (Kindai/Kyoto) cohorts. The algorithm classified the four HGSC-subtypes with mean accuracies of 0.933, 0.910, and 0.862 for the TCGA, JGOG3022A1, and Kindai/Kyoto cohorts, respectively. To compare mesenchymal transition (MT) with non-MT groups, overall survival analysis was performed in the TCGA data set. The AI-based prediction of HGSC-subtype classification in TCGA cases showed that the MT group had a worse prognosis than the non-MT group (P = 0.017). Furthermore, Cox proportional hazard regression analysis identified AI-based MT subtype classification prediction as a contributing factor along with residual disease after surgery, stage, and age. In conclusion, a robust AI-based HGSC-subtype classification algorithm was established using virtual slides of ovarian HGSC.
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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.
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Pueblos del Este de Asia , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/genética , Neoplasias Ováricas/patología , Proteína BRCA1/genética , Genes BRCA2 , Mutación , Mutación de Línea GerminalRESUMEN
Although the gross and microscopic features of squamous cell carcinoma arising from ovarian mature cystic teratoma (MCT-SCC) vary from case to case, the spatial spreading of genomic alterations within the tumor remains unclear. To clarify the spatial genomic diversity in MCT-SCCs, we performed whole-exome sequencing by collecting 16 samples from histologically different parts of two MCT-SCCs. Both cases showed histological diversity within the tumors (case 1: nonkeratinizing and keratinizing SCC and case 2: nonkeratinizing SCC and anaplastic carcinoma) and had different somatic mutation profiles by histological findings. Mutation signature analysis revealed a significantly enriched apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC) signature at all sites. Intriguingly, the spread of genomic alterations within the tumor and the clonal evolution patterns from nonmalignant epithelium to cancer sites differed between cases. TP53 mutation and copy number alterations were widespread at all sites, including the nonmalignant epithelium, in case 1. Keratinizing and nonkeratinizing SCCs were differentiated by the occurrence of unique somatic mutations from a common ancestral clone. In contrast, the nonmalignant epithelium showed almost no somatic mutations in case 2. TP53 mutation and the copy number alteration similarities were observed only in nonkeratinizing SCC samples. Nonkeratinizing SCC and anaplastic carcinoma shared almost no somatic mutations, suggesting that each locally and independently arose in the MCT. We demonstrated that two MCT-SCCs with different histologic findings were highly heterogeneous tumors with clearly different clones associated with APOBEC-mediated mutagenesis, suggesting the importance of evaluating intratumor histological and genetic heterogeneity among multiple sites of MCT-SCC.
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Carcinoma de Células Escamosas , Neoplasias Ováricas , Teratoma , Femenino , Humanos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Teratoma/genética , Teratoma/patología , Mutagénesis , GenómicaRESUMEN
The Cancer Genome Atlas (TCGA) network has clarified that ~50% of high-grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR-associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next-generation sequencing for 51 targeted genes (including 29 HR-associated genes) in 701 ovarian cancers (298 high-grade serous cases, 189 clear cell cases, 135 endometrioid cases, 12 mucinous cases, 3 low-grade serous cases, and 64 others). HRD was defined as positive when at least one HR-associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutations were 45.2% (317/701) and 18.5% (130/701), respectively, in the full analysis set. Next, we performed multivariate Cox proportional hazards regression analysis for progression-free survival (PFS) and overall survival (OS). Advanced-stage ovarian cancer patients with HRD had adjusted hazard ratios of 0.72 (95% CI, 0.55-0.94) and 0.57 (95% CI, 0.38-0.86) for PFS and OS, respectively, compared with those without HRD (p = 0.016 and 0.007). Our study demonstrated that mutations in HR-associated genes were associated with prognosis. Further studies are needed to investigate the prognostic impact of each HR-associated gene in ovarian cancer.
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Proteína BRCA1 , Neoplasias Ováricas , Femenino , Humanos , Proteína BRCA1/genética , Proteína BRCA2/genética , Recombinación Homóloga/genética , Neoplasias Ováricas/patologíaRESUMEN
BACKGROUND: This study aimed to evaluate the homologous recombination repair pathway deficiency (HRD) in ovarian high-grade serous carcinoma (HGSC). METHODS: In the ovarian cancer data from The Cancer Genome Atlas, we identified genes differentially expressed between tumours with and without HRD genomic scars and named these genes "HRDness signature". We performed SNP array, RNA sequencing, and methylation array analyses on 274 HGSC tumours for which targeted sequencing of 51 genes and clinical data were available to generate JGOG3025-TR2 dataset. The HRDness signature was tested on external datasets, including the JGOG3025-TR2 cohort, by computational scoring and machine-learning prediction. RESULTS: High scores and positive predictions of the HRDness signature were significantly associated with BRCA alterations, genomic scar scores, and better survival. On the other hand, among cases with high scores and/or positive predictions, those with BRCA1 methylation showed poorer survival. In the JGOG3025-TR2 cohort, HRD status was significantly associated with the use of olaparib after relapse and progression-free survival after its initiation. CONCLUSIONS: The HRDness gene expression signature is associated with a good prognosis, while BRCA1 methylation is associated with a poor prognosis. The newly generated JGOG3025-TR2 dataset will be useful in future HGSC studies.
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Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Pronóstico , Mutación , Transcriptoma , Proteína BRCA2/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/genética , Cistadenocarcinoma Seroso/genéticaRESUMEN
The metabolites in the plasma serve as potential biomarkers of disease. We previously established an early-onset diabetes mouse model, Ins2+/Q104del Kuma mice, under a severe immune-deficient (Rag-2/Jak3 double-deficient in BALB/c) background. Here, we revealed the differences in plasma amino acid profiles between Kuma and the wild-type mice. We observed an early reduction in glucogenic and ketogenic amino acids, a late increase in branched-chain amino acids (BCAAs) and succinyl CoA-related amino acids, and a trend of increasing ketogenic amino acids in Kuma mice than in the wild-type mice. Kuma mice exhibited hyperglucagonemia at high blood glucose, leading to perturbations in plasma amino acid profiles. The reversal of blood glucose by islet transplantation normalized the increases of the BCAAs and several aspects of the altered metabolic profiles in Kuma mice. Our results indicate that the Kuma mice are a unique animal model to study the link between plasma amino acid profile and the progression of diabetes for monitoring the therapeutic effects.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Ratones , Animales , Glucemia/metabolismo , Insulina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Aminoácidos , Aminoácidos de Cadena Ramificada/metabolismoRESUMEN
Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma.
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Carcinosarcoma , Neoplasias Endometriales , Neoplasias Uterinas , Femenino , Humanos , Recurrencia Local de Neoplasia , Neoplasias Endometriales/terapia , Neoplasias Endometriales/patología , Carboplatino/uso terapéutico , Terapia Combinada , Carcinosarcoma/terapia , Carcinosarcoma/tratamiento farmacológico , Neoplasias Uterinas/patologíaRESUMEN
Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma.
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Coriocarcinoma , Enfermedad Trofoblástica Gestacional , Neoplasias Uterinas , Embarazo , Femenino , Humanos , Neoplasias Uterinas/patología , Resultado del Tratamiento , Estudios Retrospectivos , Coriocarcinoma/terapia , Coriocarcinoma/patología , Enfermedad Trofoblástica Gestacional/tratamiento farmacológicoRESUMEN
BACKGROUND: Although several studies have found significant relationships between autistic traits and depression/anxiety, the relationships between autistic traits and postpartum depression/anxiety remain unclear. Moreover, few studies have examined the relationships between autistic traits and mother-infant bonding while considering depression or anxiety. METHODS: This study used a cross-sectional data analysis design. Participants were 2692 women who completed the Autism-Spectrum Quotient (AQ), Hospital Anxiety and Depression Scale (HADS), and Mother-to-Infant Bonding Scale (MIBS) at 1 month postpartum. We performed path analysis that included parity, the five AQ subscales (social skills, attention switching, attention to detail, communication, and imagination), both HADS subscales (anxiety and depression), and the two MIBS subscales (lack of affection and anger and rejection). RESULTS: Our path analysis revealed that higher scores for social skills, attention switching, communication, and imagination were associated with higher scores for depression. Higher scores for social skills, attention switching, attention to detail, and communication were associated with higher scores for anxiety. Moreover, difficulties in social skills and imagination were associated with failure of maternal-infant bonding. However, more attention to detail was associated with better maternal-infant bonding. CONCLUSIONS: This study suggests that maternal autistic traits are related to anxiety and depression to a certain degree, but only slightly related to maternal-infant bonding at 1 month postpartum. To improve autistic women's quality of life and that of their newborns, perinatal mental health issues such as anxiety, depression, and maternal-fetal bonding difficulties should be appropriately addressed.
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Trastorno Autístico , Depresión Posparto , Embarazo , Humanos , Femenino , Lactante , Recién Nacido , Depresión , Estudios Transversales , Calidad de Vida , Periodo Posparto , Depresión Posparto/psicología , Ansiedad/psicología , Madres/psicología , Apego a Objetos , Relaciones Madre-HijoRESUMEN
PURPOSE: In Japan, Japan's Ministry of Health, Labor, and Welfare decided to suspend govermental recommendation for HPV vaccination in FY 2013. The HPV vaccination rate for those born in FY 2000 or thereafter declined dramatically. In 2021, the "suspension of recommendation" ended. The catch-up vaccinations for the unvaccinated have been offered nationwide from FY 2022 to FY 2024. We aimed to quantify the vaccination intentions and characteristics of those young women now eligible for catch-up vaccination. METHODS: In February of 2022, we conducted an internet survey targeted women who were born in 1997-2004 but who had not yet been HPV vaccinated. RESULTS: We received 1,648 valid responses. 41.6% of the respondents wanted to uptake the catch-up HPV vaccination, 29.7% were undecided, and 28.7% did not want to be vaccinated. The intention to uptake catch-up HPV vaccination was associated with a good history of gynecological visits, intention to receive cervical cancer screening, sexual activity, degree of anxiety about cervical cancer, familiarity with problems associated with cervical cancer, experience with vaccination recommendations, and knowledge about cervical cancer (p < 0.05, respectively). In the vaccinated generation, the proportion of the group that did not want to be vaccinated was significantly higher (p < 0.05). In the vaccine-suspended generation, the proportion of the group that wanted to be vaccinated was significantly higher (p < 0.05). CONCLUSION: Our survey revealed that catch-up vaccination intentions differed depending on the vaccination environment. It is necessary for all organizations involved with HPV vaccination, such as government, medical institutions, and educational institutions, to make recommendations based on an understanding of the characteristics of the "vaccinated generation" and the "vaccine-suspended generation".
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Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino , Femenino , Humanos , Neoplasias del Cuello Uterino/prevención & control , Intención , Japón , Infecciones por Papillomavirus/prevención & control , Detección Precoz del Cáncer , Encuestas y Cuestionarios , Vacunación , Internet , Vacunas contra Papillomavirus/uso terapéuticoRESUMEN
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.
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Anemia , Antieméticos , Neoplasias Ováricas , Trombocitopenia , Humanos , Femenino , Carboplatino/efectos adversos , Antieméticos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Ováricas/patología , Paclitaxel , Anemia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
OBJECTIVES: We aimed to clarify the accuracy of pregnant women's knowledge and understanding regarding infectious disease screening in early pregnancy and clarify the roles that should be played by health care providers in promoting the health of pregnant women and their children. METHODS: A cross-sectional questionnaire survey was conducted in 25 hospitals across Japan from May 2018 to September 2019. We compared the agreement rates regarding screening results for hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, human T-cell leukemia virus-1 (HTLV-1), and cervical cytology in the medical records and understanding of their results by pregnant women. We then investigated whether participants had knowledge regarding the risk of mother-to child transmission in these diseases and factors associated with their knowledge. RESULTS: We enrolled 2,838 respondents in this study. The rates of agreement for HBV and cervical cancer screening related to human papillomavirus infection were "substantial," those for syphilis was "moderate," and those for HCV and HTLV-1 were "fair," according to the Kappa coefficient. The rate of knowledge regarding mother-to-child transmission of syphilis was highest (37.0%); this rate for the other items was approximately 30%. Increased knowledge was associated with higher educational level and higher annual income. CONCLUSIONS FOR PRACTICE: Pregnant women in Japan had generally good levels of understanding regarding their results in early-pregnancy infectious disease screening. However, they had insufficient knowledge regarding mother-to-child transmission of these diseases. Health care providers should raise awareness in infectious disease prevention among pregnant women and the general public, providing appropriate measures and implementing effective perinatal checkups and follow-ups for infectious diseases.
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Hepatitis B , Hepatitis C , Transmisión Vertical de Enfermedad Infecciosa , Complicaciones Infecciosas del Embarazo , Sífilis , Mujeres Embarazadas , Humanos , Femenino , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/prevención & control , Embarazo , Adulto , Estudios Transversales , Japón/epidemiología , Conocimientos, Actitudes y Práctica en Salud , Virus de la Hepatitis B , Hepacivirus , Tamizaje MasivoRESUMEN
AIM: To evaluate changes of treatment strength and its impact on prognosis in older patients with ovarian cancer. METHODS: We compared relative dose intensity (RDI) as a representative of treatment strength, prognosis, and other features between older (≥65 years) and younger patients (<65 years) retrospectively. Seventy-seven older patients of 301 who received dose-dense-paclitaxel-carboplatin (dTC) and 93 older patients of 304 who received conventional-paclitaxel-carboplatin (cTC) from the Japanese Gynecologic Oncology Group (JGOG) 3016 clinical trial were analyzed. RESULTS: The RDI of older patients was lower than that of younger patients in cTC (87.4% vs. 90.8%, p = 0.009) but not in dTC (79.0% vs. 81.2%, p = 0.205). In both regimens, older patients had worse overall survival than younger patients: hazard ratio [HR] = 1.80; 95% confidence interval [CI]: 1.25-2.59; p = 0.001 for dTC, and HR = 1.59; 95% CI: 1.15-2.19; p = 0.04 for cTC. However, the RDI was not determined as a prognostic factor statistically. The prognostic factors identified by multivariate analysis for both regimens were clinical stage and residual disease; for dTC were age, performance status, and serum albumin; and for cTC was white blood cell count. There was no difference in neutropenia observed between age groups in either regimen. CONCLUSIONS: The RDI of older patients varies according to the administered schedule and is not always lower than that of younger patients. Older patients with comparable treatment strength to younger patients in the dTC group did not accomplish the same level of prognosis as younger patients. Other biologic factors attributable to aging may affect prognosis.
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Neoplasias Ováricas , Humanos , Femenino , Anciano , Carboplatino , Pronóstico , Estudios Retrospectivos , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Japanese girls aged 12-16 years are offered free human papillomavirus (HPV) vaccination and cervical cancer screening is conducted with cytology and not HPV testing from the age of 20 years. So far, no study has analyzed the effect of HPV vaccination against cervical precancers considering HPV infection status and sexual activity. We aimed to analyze the vaccine effectiveness (VE) against HPV infection and cytological abnormalities, adjusted for sexual activity. This study comprised women aged 20-26 years who underwent cervical screening in Niigata. We obtained HPV vaccination status from municipal records and a questionnaire along with information concerning sexual activity. Of 5194 women registered for this study, final analyses included 3167 women in the vaccinated group (2821 vaccinated women prior to sexual debut) and 1386 women in the unvaccinated group. HPV 16/18 (0.2% vs 3.5%), 31/45/52 (3.4% vs 6.6%), and 31/33/45/52/58 (5.0% vs 9.3%) positive rates were significantly lower in the vaccinated group (P < 0.001). No women vaccinated before sexual debut had HPV 16/18-related cytological abnormalities. VE for HPV 16/18 infection and high-grade cytological abnormalities in women vaccinated prior to sexual debut were 95.8% (95% CI 81.9-99.0%; P < 0.001) and 78.3% (95% CI 11.3-94.7%; P = 0.033), respectively, in multivariate analyses adjusted for age and number of sexual partners. However, analyses of all vaccinated women did not show significant effectiveness against cytological abnormalities. Our results showed the effectiveness of HPV vaccine against high-grade cervical cytological abnormalities and the importance of the vaccination before sexual debut.
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Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino , Detección Precoz del Cáncer , Femenino , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Japón , Análisis Multivariante , Papillomaviridae , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/uso terapéutico , Conducta Sexual , Neoplasias del Cuello Uterino/prevención & control , VacunaciónRESUMEN
We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open-label, phase II trial (JGOG3023), patients were randomized 1:1 to a single-agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m2 administered intravenously], topotecan [1.25 mg/m2 intravenously], paclitaxel [80 mg/m2 intravenously], or gemcitabine [1000 mg/m2 intravenously]) or single-agent chemotherapy + bevacizumab (15 mg/m2 intravenously). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator-assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32-0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38-1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment-related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification.
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Antineoplásicos/administración & dosificación , Bevacizumab/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Anciano , Antineoplásicos/efectos adversos , Bevacizumab/efectos adversos , Bevacizumab/farmacología , Femenino , Humanos , Persona de Mediana Edad , Platino (Metal)/uso terapéutico , Nivel de Atención , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
In Japan, public funding for HPV vaccination began in 2010 for girls aged 13-16 years (birth cohort years 1994-1997) and women born in 1994 who turned 25 in 2019. We aimed to verify the long-term effectiveness of the bivalent HPV vaccine in women aged 25 years. Subjects were women aged 25-26 years who underwent cervical cancer screening and HPV testing in Niigata from 2019 to 2020 (birth cohort years 1993-1994). Information on vaccination status and sexual behavior was obtained from a questionnaire and municipal records. We compared the HPV infection rates of the vaccinated and unvaccinated groups. Of the 429 registrants, 150 (35.0%) and 279 (65.0%) were vaccinated and unvaccinated, respectively. The average period from HPV vaccination to HPV testing was 102.7 months (8.6 years), with a median of 103 months (range 92-109 months). The HPV high-risk infection rate was 21.3% (32/150) in the vaccinated group and 23.7% (66/279) in the unvaccinated group (P = 0.63). The HPV16/18 infection rate was 0% (0/150) in the vaccinated group and 5.4% (15/279) in the unvaccinated group, showing a significant difference (P = 0.0018), and the vaccine effectiveness was 100%. The cross-protective type HPV31/45/52 infection rate in the vaccinated group was significantly lower than that in the unvaccinated group (3.3% vs. 10.0%, P = 0.013). There was no significant difference in the mean age at sexual debut and the number of previous sexual partners between the two groups. We have demonstrated the long-term 9-year effectiveness of the bivalent vaccine against HPV infection for the first time in Japan.
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Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Neoplasias del Cuello Uterino , Adulto , Detección Precoz del Cáncer , Femenino , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Humanos , Japón/epidemiología , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/uso terapéutico , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/prevención & control , VacunaciónRESUMEN
This study evaluated the feasibility and efficacy of three postoperative adjuvant chemotherapy regimens for endometrial cancer. Endometrioid cancer patients with intermediate-risk stage I and II or high-risk stage III and IV disease were randomly assigned to receive six cycles of either paclitaxel-epirubicin-carboplatin (TEC), paclitaxel-anthracycline (doxorubicin)-carboplatin (TAC), or dose-dense paclitaxel-carboplatin (ddTC). The primary end-point was the completion rate (CRate) of six cycles of treatment. The secondary end-points were progression-free survival (PFS) and overall survival (OS). One hundred and one patients were treated as follows: 33 received TEC, 33 TAC, and 35 ddTC. The CRates for TEC, TAC, and ddTC were 94%, 64%, and 69%, respectively (P = .005). The TEC CRate was significantly higher than for the other two groups. However, the PFS and OS outcomes were not statistically different between the three groups. The 2-year survival rates were 94%, 97%, and 97% for TEC, TAC, and ddTC, respectively. When compared to the current standard treatments for endometrial cancer, TEC is a promising candidate for a phase III trial based on its significantly superior CRate and equivalent PFS and OS. This study is registered with UMIN Clinical Trials Registry (UMIN000008911).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/efectos adversos , Quimioterapia Adyuvante , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Humanos , Estadificación de Neoplasias , Paclitaxel/uso terapéuticoRESUMEN
Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow-up, 11.8 [range, 1.1-26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63-1.73) in patients with pMMR and 0.81 (0.50-1.31) in all-comers. Hazard ratios for OS were 0.74 (0.41-1.34) with pMMR and 0.59 (0.33-1.04) for all-comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE-775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum-based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Endometriales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Doxorrubicina/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Femenino , Humanos , Japón , Paclitaxel , Compuestos de Fenilurea , QuinolinasRESUMEN
Endometriosis is a benign gynecologic condition, acting as a precursor of certain histological subtypes of ovarian cancers. The epithelial cells of endometriotic tissues and normal uterine endometrium accumulated somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and Kirsten rat sarcoma (KRAS) proto-oncogene. To determine the genomic characteristic of endometriotic epithelial cells and normal uterine endometrium and to identify the predominant mutational process acting on them, we studied the somatic mutation profiles obtained from whole exome sequencing of 14 endometriotic epithelium and 11 normal uterine endometrium tissues and classified them into mutational signatures. We observed that single base substitutions 2/13 (SBS), attributed to Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit (APOBEC) induced mutagenesis, were significant in endometriotic tissues, but not in the normal uterine endometrium. Additionally, the larger number and wider allele frequency distribution of APOBEC signature mutations, compared to cancer-associated driver mutations in endometriotic epithelium suggested APOBEC mutagenesis as an important source of mutational burden and heterogeneity in endometriosis. Further, the relative risk of enriched APOBEC signature mutations was higher in endometriosis patients who were carriers of APOBEC3A/3B germline deletion, a common polymorphism in East Asians which involves the complete loss of APOBEC3B coding region. Our results illustrate the significance of APOBEC induced mutagenesis in driving the genomic heterogeneity of endometriosis.
Asunto(s)
Endometriosis , Neoplasias Ováricas , Citidina Desaminasa/genética , Endometriosis/genética , Endometriosis/patología , Endometrio/patología , Femenino , Genómica , Humanos , Antígenos de Histocompatibilidad Menor , Mutagénesis , Mutación , Neoplasias Ováricas/genética , ProteínasRESUMEN
We previously reported that L63X and Q934X are BRCA1 common founder variants in Japan. So far, there have been no reports of a correlation between such BRCA common variants and the risk of BRCA-related cancers. In this analysis, we investigated the correlation between the risk of ovarian cancer (OC) and BRCA recurrent pathogenic variants. We examined the database of the Japanese organization of hereditary breast and ovarian cancer. The database contained 3517 probands who underwent BRCA genetic testing. Among them, 11.1% (392/3517) had germline BRCA1 pathogenic variant, and 8.3% (293/3517) had BRCA2 pathogenic variant. We calculated the OC prevalence, breast cancer (BC) prevalence, and the ratio of OC to BC within second-degree relatives. The ratio of OC to BC in Q934X family members was significantly higher than that in the overall BRCA1 family members (0.80 vs.0.52: p = 0.038), and the ratio in STOP799 was 0.42, which was relatively lower than the overall BRCA1 value. Both Q934X and STOP799 are located in the ovarian cancer cluster region (OCCR), however there seems to be a difference in the risk of OC. R2318X family members had a significant higher ratio of OC to BC at 0.32 than the overall BRCA2 value of 0.13 (p = 0.012). R2318X is known to be located in the OCCR. This is the first report to investigate the correlation between BRCA recurrent variants and the risk of OC in Japan. The family members of probands with Q934X or R2318X have a higher risk of OC than that with other BRCA variants.