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Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
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Neoplasias da Mama , Linhagem da Célula , Células Clonais , Evolução Molecular , Mutagênese , Mutação , Adolescente , Adulto , Feminino , Humanos , Adulto Jovem , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem da Célula/genética , Células Clonais/metabolismo , Células Clonais/patologia , Epigênese Genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio/patologia , Microdissecção , Taxa de Mutação , Pré-Menopausa , Microambiente TumoralRESUMO
In vitro oogenesis is key to elucidating the mechanism of human female germ-cell development and its anomalies. Accordingly, pluripotent stem cells have been induced into primordial germ cell-like cells and into oogonia with epigenetic reprogramming, yet further reconstitutions remain a challenge. Here, we demonstrate ex vivo reconstitution of fetal oocyte development in both humans and cynomolgus monkeys (Macaca fascicularis). With an optimized culture of fetal ovary reaggregates over three months, human and monkey oogonia enter and complete the first meiotic prophase to differentiate into diplotene oocytes that form primordial follicles, the source for oogenesis in adults. The cytological and transcriptomic progressions of fetal oocyte development in vitro closely recapitulate those in vivo. A comparison of single-cell transcriptomes among humans, monkeys, and mice unravels primate-specific and conserved programs driving fetal oocyte development, the former including a distinct transcriptomic transformation upon oogonia-to-oocyte transition and the latter including two active X chromosomes with little X-chromosome upregulation. Our study provides a critical step forward for realizing human in vitro oogenesis and uncovers salient characteristics of fetal oocyte development in primates.
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Meiose , Oogênese , Animais , Feminino , Humanos , Macaca fascicularis , Camundongos , Oócitos , Oogênese/fisiologia , OvárioRESUMO
Tumor-infiltrating lymphocytes (TILs) are associated with improved survival in patients with epithelial ovarian cancer. However, TIL evaluation has not been used in routine clinical practice because of reproducibility issues. The current study developed two convolutional neural network models to detect TILs and to determine their spatial location in whole slide images, and established a spatial assessment pipeline to objectively quantify intraepithelial and stromal TILs in patients with high-grade serous ovarian carcinoma. The predictions of the established models showed a significant positive correlation with the number of CD8+ T cells and immune gene expressions. Patients with a higher density of intraepithelial TILs had a significantly prolonged overall survival and progression-free survival in multiple cohorts. On the basis of the density of intraepithelial and stromal TILs, patients were classified into three immunophenotypes: immune inflamed, excluded, and desert. The immune-desert subgroup showed the worst prognosis. Gene expression analysis showed that the immune-desert subgroup had lower immune cytolytic activity and T-cell-inflamed gene-expression profile scores, whereas the immune-excluded subgroup had higher expression of interferon-γ and programmed death 1 receptor signaling pathway. The established evaluation method provided detailed and comprehensive quantification of intraepithelial and stromal TILs throughout hematoxylin and eosin-stained slides. It has potential for clinical application for personalized treatment of patients with ovarian cancer.
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Cistadenocarcinoma Seroso , Aprendizado Profundo , Linfócitos do Interstício Tumoral , Neoplasias Ovarianas , Humanos , Feminino , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/genética , Pessoa de Meia-Idade , Idoso , Prognóstico , Células Estromais/patologia , Células Estromais/imunologia , Células Estromais/metabolismo , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismoRESUMO
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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Inteligência Artificial , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/classificação , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/classificação , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Idoso , Aprendizado Profundo , Algoritmos , Adulto , Linfócitos do Interstício Tumoral/patologia , PrognósticoRESUMO
BACKGROUND: Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear. METHODS: Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC. RESULTS: Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC. CONCLUSIONS: Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs.
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Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Metilação de DNA , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/classificação , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Ciclina E/genética , Pessoa de Meia-Idade , Variações do Número de Cópias de DNA , Proteína BRCA2/genética , Gradação de Tumores , Proteína BRCA1/genética , Proteínas Oncogênicas/genética , Idoso , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/classificação , Polimorfismo de Nucleotídeo Único , Adulto , Prognóstico , MultiômicaRESUMO
The intervillous space of human placenta is filled with maternal blood, and villous trophoblasts are constantly exposed to the shear stress generated by maternal blood pressure and flow throughout the entire gestation period. However, the effects of shear stress on villous trophoblasts and their biological significance remain unknown. Here, using our recently established naïve human pluripotent stem cells-derived cytotrophoblast stem cells (nCTs) and a device that can apply arbitrary shear stress to cells, we investigated the impact of shear stress on early-stage trophoblasts. After 72 h of exposure to 10 dyn/cm2 shear stress, nCTs became fused and multinuclear, and mRNA expression of the syncytiotrophoblast (ST) markers, such as glial cell missing 1, endogenous retrovirus group W member 1 envelope, chorionic gonadotropin subunit beta 3, syndecan 1, pregnancy specific beta-1-glycoprotein 3, placental growth factor, and solute carrier family 2 member 1 were significantly upregulated compared to static conditions. Immunohistochemistry showed that shear stress increased fusion index, human chorionic gonadotropin secretion, and human placental lactogen secretion. Increased microvilli formation on the surface of nCTs under flow conditions was detected using scanning electron microscopy. Intracellular cyclic adenosine monophosphate significantly increased under flow conditions. Moreover, transcriptome analysis of nCTs subjected to shear stress revealed that shear stress upregulated ST-specific genes and downregulated CT-specific genes. Collectively, these findings indicate that shear stress promotes the differentiation of nCTs into ST.
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Células-Tronco Pluripotentes Induzidas , Placenta , Feminino , Gravidez , Humanos , Placenta/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Fator de Crescimento Placentário/metabolismo , Trofoblastos/metabolismo , Gonadotropina Coriônica/farmacologia , Gonadotropina Coriônica/metabolismo , Diferenciação CelularRESUMO
Primary peritoneal cancer has characteristics similar to high-grade serous carcinomas of ovarian and fallopian tube origin. However, the relationship between endometriosis and primary peritoneal cancer is not well understood. This study focuses on a case of peritoneal cancer in a patient who had undergone hysterectomy and bilateral salpingo-oophorectomy 5 yr before. In addition to morphology, there was a positive for TP53 in immunohistochemistry and homologous recombination deficiency test, which were similar to high-grade serous carcinomas. However, WT1 was negative in the tumor, and extensive endometriosis coexisted. To reveal the clonal relationship between tumor and endometriosis, we dissected 3 sites each from the tumor and endometriosis and performed whole-exome sequencing analysis. As a result, we found that the tumors were of identical origin. Contrarily, no shared mutations were found in the 3 endometriosis sites. Furthermore, several shared mutations were found between the tumor and 1 endometriosis tissue, showing that the tumor and 1 ectopic endometrial gland originated from the same clone. This study indicates that several peritoneal cancers may be derived from endometriosis. We should consider the possibility of more diverse origins of peritoneal cancer than we speculated before.
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OBJECTIVE: To examine the association between intrauterine manipulator use and pathological factors and oncologic outcomes in patients with endometrial cancer who had laparoscopic hysterectomy in Japan. METHODS: This was a nationwide retrospective cohort study of the tumor registry of the Japan Society of Obstetrics and Gynecology. Study population was 3846 patients who had laparoscopic hysterectomy for endometrial cancer from January 2015 to December 2017. An automated 1-to-1 propensity score matching with preoperative and intraoperative demographics was performed to assess postoperative pathological factors associated with the intrauterine manipulator. Survival outcomes were assessed by accounting for possible pathological mediators related to intrauterine manipulator use. RESULTS: Most patients had preoperative stage I disease (96.5%) and grade 1-2 endometrioid tumors (81.9%). During the study period, 1607 (41.8%) patients had intrauterine manipulator use and 2239 (58.2%) patients did not. In the matched cohort, the incidences of lymphovascular space invasion in the hysterectomy specimen were 17.8% in the intrauterine manipulator group and 13.3% in the non-manipulator group. Intrauterine manipulator use was associated with a 35% increased odds of lymphovascular space invasion (adjusted odds ratio 1.35, 95% confidence interval (CI) 1.08 to 1.69). The incidences of malignant cells identified in the pelvic peritoneal cytologic sample at hysterectomy were 10.8% for the intrauterine manipulator group and 6.4% for the non-manipulator group. Intrauterine manipulator use was associated with a 77% increased odds of malignant peritoneal cytology (adjusted odds ratio 1.77, 95% Cl 1.29 to 2.31). The 5 year overall survival rates were 94.2% for the intrauterine manipulator group and 96.6% for the non-manipulator group (hazard ratio (HR) 1.64, 95% Cl 1.12 to 2.39). Possible pathological mediators accounted HR was 1.36 (95%Cl 0.93 to 2.00). CONCLUSION: This nationwide analysis of predominantly early stage, low-grade endometrial cancer in Japan suggested that intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer may be associated with an increased risk of lymphovascular space invasion and malignant peritoneal cytology. Possible mediator effects of intrauterine manipulator use on survival warrant further investigation, especially with a prospective setting.
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Neoplasias do Endométrio , Laparoscopia , Feminino , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Neoplasias do Endométrio/cirurgia , Neoplasias do Endométrio/patologia , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversos , Estadiamento de NeoplasiasRESUMO
BACKGROUND: The actual status of comprehensive genomic profiling (CGP) applications in Japan has not been clarified. We conducted a multicenter study to investigate the real-world application of CGP in gynecological malignancies. METHODS: Nine designated cancer hospitals participated in this study. Patients who underwent CGP in 2020-2021 were assigned to the CGP group (n = 134). For the population that would have been eligible for CGP, patients who received initial treatment in 2015-2016 and were either alive with disease or died of disease at 5 years follow up were included in the control group (n = 316). We compared clinicopathological characteristics including tumor type (cervix, corpus, ovary, and others including sarcoma) and age. We also investigated the context of CGP-recommended treatment. RESULTS: The CGP group had significantly fewer cervical cases and more others cases (cervix/corpus/ovary/others: CGP, 22/44/56/12; control, 89/79/142/6; p = 0.0003). The CGP group was significantly younger than the control group (median: CGP, 54.0; control, 65.0; p < 0.0001). Subgroup analyses revealed that patients with cervical and ovarian cancers were significantly younger in the CGP group. Among the CGP group, 17 patients (12.7%) received CGP-recommended treatments, 15 of which were not covered by public insurance. The survival time after CGP in 17 patients was longer than in the other 117 cases (median 21 vs. 11 months). CONCLUSION: There was significant selection bias in tumor type and age for the application of CGP for gynecological malignancies in clinical practice in Japan. While CGP often recommended drugs not covered by public insurance, prognosis can be improved by use of CGP.
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BACKGROUND: Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in mismatch repair (MMR) genes, which predisposes to various types of cancers showing deficient MMR (dMMR). Identification of LS probands is crucial to reduce cancer-related deaths in affected families. Although universal screening is recommended for colorectal and endometrial cancers, and age-restricted screening is proposed as an alternative, LS screening covering a broader spectrum of cancer types is needed. In the current study, we elucidated the rate of dMMR tumors and evaluated the outcome of LS screening in young-onset extra-colorectal LS-associated cancers. METHODS: Immunohistochemistry for MMR proteins were retrospectively performed in a total of 309 tissue samples of endometrial, non-mucinous ovarian, gastric, urothelial, pancreatic, biliary tract, and adrenal cancers in patients < 50 years of age. Clinicopathological information and the results of genetic testing were obtained from medical charts. RESULTS: There were 24 dMMR tumors (7.8%) including 18 endometrial, three ovarian, two urothelial, and one gastric cancer. Co-occurrence of colorectal cancer and family history of LS-associated cancers was significantly enriched in patients with dMMR tumors. Among the 16 patients with dMMR tumors who were informed of the immunohistochemistry results, five with endometrial and one with urothelial cancer were diagnosed as LS with positive pathogenic variants in MMR genes. CONCLUSIONS: We report the outcome of immunohistochemistry for MMR proteins performed in multiple types of young-onset extra-colorectal LS-associated cancers. Our study demonstrates the feasibility of a comprehensive LS screening program incorporating young-onset patients with various types of extra-colorectal LS-associated cancers.
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Neoplasias Colorretais Hereditárias sem Polipose , Reparo de Erro de Pareamento de DNA , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reparo de Erro de Pareamento de DNA/genética , Detecção Precoce de Câncer/métodos , Testes Genéticos , Idade de Início , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Adulto JovemRESUMO
There have been no reported cases of neuroendocrine carcinoma (NEC) of the cervix with pagetoid spread (Pag-S). A 44-year-old woman came to our department because of abnormal cytology that persisted immediately after a radical hysterectomy for NEC of the cervix. A mapping biopsy in a large area from the vaginal wall to the vulva revealed that synaptophysin/Ki-67-positive tumor cells were scattered within the epithelium in multiple areas, suggesting a wide Pag-S of NEC. Because tumor cells were found beyond the vaginal wall, the anterior pelvic exenteration was performed. Since we could pathologically confirm the complete resection and no distant metastases were detected, no adjuvant therapy was performed. Four years have passed since the initial treatment without any tumor recurrence. It is known that the prognosis of NEC of the cervix that invades beyond the cervix is poor; however, if there is a Pag-S pattern, a radical surgical treatment can be considered.
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Carcinoma Neuroendócrino , Neoplasias do Colo do Útero , Feminino , Humanos , Adulto , Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Recidiva Local de Neoplasia , Carcinoma Neuroendócrino/cirurgia , Carcinoma Neuroendócrino/patologia , PrognósticoRESUMO
PURPOSES: This study investigates the clinical significance of the anterior parametrical invasion in surgically treated patients with cervical squamous cell carcinoma (SCC). METHODS: We included patients diagnosed with cervical SCC with local lesions classified as T2b, who were treated at our department between January 2006 and December 2020. We evaluated the degree of anterior invasion using pretreatment magnetic resonance imaging and divided patients into three groups: partial, equivocal, and full invasion. The frequency of recurrence within 3 years (early recurrence) and overall prognosis were assessed. RESULTS: There were 12, 24, and 46 cases in the partial equivocal, and full invasion groups, respectively. Neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy was the mainstay of treatment across all groups (7, 17, and 27 cases, respectively). Although the frequency of early recurrence tended to be worse in the full group (partial; 2/7 cases, equivocal; 3/17 cases and full; 9/27 cases), all early local recurrence cases in the full group (four cases) responded well to the subsequent treatment. As for overall survival, the full invasion group had the best prognosis among the three groups. CONCLUSIONS: In surgical treatment, although full anterior invasion may increase the risk of early local recurrence, it was considered to have little prognostic impact.
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Carcinoma de Células Escamosas , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/cirurgia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/terapia , Pessoa de Meia-Idade , Adulto , Idoso , Prognóstico , Estudos Retrospectivos , Imageamento por Ressonância Magnética , Terapia Neoadjuvante , Quimioterapia AdjuvanteRESUMO
Telesurgery is expected to improve medical access in areas with limited resources, facilitate the rapid dissemination of new surgical procedures, and advance surgical education. While previously hindered by communication delays and costs, recent advancements in information technology and the emergence of new surgical robots have created an environment conducive to societal implementation. In Japan, the legal framework established in 2019 allows for remote surgical support under the supervision of an actual surgeon. The Japan Surgical Society led a collaborative effort, involving various stakeholders, to conduct social verification experiments using telesurgery, resulting in the development of a Japanese version of the "Telesurgery Guidelines" in June 2022. These guidelines outline requirements for medical teams, communication environments, robotic systems, and security measures for communication lines, as well as responsibility allocation, cost burden, and the handling of adverse events during telesurgery. In addition, they address telementoring and full telesurgery. The guidelines are expected to be revised as needed, based on the utilization of telesurgery, advancements in surgical robots, and improvements in information technology.
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Sociedades Médicas , Telemedicina , Japão , Humanos , Procedimentos Cirúrgicos Robóticos/normas , Equipe de Assistência ao Paciente , Tecnologia da Informação , Guias de Prática Clínica como Assunto , Cirurgia Geral/educaçãoRESUMO
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.
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Anemia , Neoplasias do Colo do Útero , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1 , Quimiorradioterapia/efeitos adversos , Método Duplo-Cego , Recidiva Local de Neoplasia , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
In the article titled "IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer" in 2015, we showed that PD-L1 expression is induced by IFN-γ from lymphocytes in the tumour microenvironment. This article proposed that PD-L1 expression in cancer cells is not stable but varies among cases, or even within a case, which is influenced by the stromal infiltration of cytotoxic lymphocytes. Immune-checkpoint inhibitors, especially anti-PD-1/PD-L1 therapies, are now widely used to treat various types of cancer. Predictive biomarkers for the efficacy of immune-checkpoint inhibitors include PD-L1 expression, MSI/mismatch repair deficiency and high tumour mutation burden. However, clinical trials have proven that their use in ovarian cancer is still challenging. Reliable biomarkers and new treatment strategies may be sought by elucidating the complex immune microenvironment of ovarian cancer. Although the interaction between cytotoxic lymphocytes and PD-1/PD-L1 on tumour cells is at the centre of therapeutic targets, other immune checkpoints and various immunosuppressive cells also play important roles in ovarian cancer. Targeting these role players in combination with PD-1/PD-L1 blockade may be a promising therapeutic strategy.
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Neoplasias Encefálicas , Neoplasias Ovarianas , Humanos , Feminino , Antígeno B7-H1/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Interferon gama/metabolismo , Linfócitos/patologia , Microambiente TumoralRESUMO
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 Ovarianas , Feminino , Humanos , Prognóstico , Mutação , Transcriptoma , Proteína BRCA2/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/genética , Cistadenocarcinoma Seroso/genéticaRESUMO
OBJECTIVES: To build preoperative prediction models with and without MRI for regional lymph node metastasis (r-LNM, pelvic and/or para-aortic LNM (PENM/PANM)) and for PANM in endometrial cancer using established risk factors. METHODS: In this retrospective two-center study, 364 patients with endometrial cancer were included: 253 in the model development and 111 in the external validation. For r-LNM and PANM, respectively, best subset regression with ten-time fivefold cross validation was conducted using ten established risk factors (4 clinical and 6 imaging factors). Models with the top 10 percentile of area under the curve (AUC) and with the fewest variables in the model development were subjected to the external validation (11 and 4 candidates, respectively, for r-LNM and PANM). Then, the models with the highest AUC were selected as the final models. Models without MRI findings were developed similarly, assuming the cases where MRI was not available. RESULTS: The final r-LNM model consisted of pelvic lymph node (PEN) ≥ 6 mm, deep myometrial invasion (DMI) on MRI, CA125, para-aortic lymph node (PAN) ≥ 6 mm, and biopsy; PANM model consisted of DMI, PAN, PEN, and CA125 (in order of correlation coefficient ß values). The AUCs were 0.85 (95%CI: 0.77-0.92) and 0.86 (0.75-0.94) for the external validation, respectively. The model without MRI for r-LNM and PANM showed AUC of 0.79 (0.68-0.89) and 0.87 (0.76-0.96), respectively. CONCLUSIONS: The prediction models created by best subset regression with cross validation showed high diagnostic performance for predicting LNM in endometrial cancer, which may avoid unnecessary lymphadenectomies. CLINICAL RELEVANCE STATEMENT: The prediction risks of lymph node metastasis (LNM) and para-aortic LNM can be easily obtained for all patients with endometrial cancer by inputting the conventional clinical information into our models. They help in the decision-making for optimal lymphadenectomy and personalized treatment. KEY POINTS: â¢Diagnostic performance of lymph node metastases (LNM) in endometrial cancer is low based on size criteria and can be improved by combining with other clinical information. â¢The optimized logistic regression model for regional LNM consists of lymph node ≥ 6 mm, deep myometrial invasion, cancer antigen-125, and biopsy, showing high diagnostic performance. â¢Our model predicts the preoperative risk of LNM, which may avoid unnecessary lymphadenectomies.
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BACKGROUND: Estrogen therapy (ET) plays a key role in maintaining the post-surgical quality of life of patients with endometrial cancer. This study investigated the reality of the use of ET after endometrial cancer surgery in Japan. METHODS: Using a healthcare database in Japan, patients who underwent surgery for endometrial cancer between the ages of 40 and 59 years from January 2006 to March 2021 were included. The cumulative prescriptions of ET after endometrial cancer surgeries in patients who had received chemotherapy or radiation therapy (adj-group) and those who did not (non-adj-group) was estimated using the Kaplan-Meier method. RESULTS: Of the 1475 patients, 115 received ET, among whom transdermal estradiol was initiated in 100 (87.0%) individuals. The cumulative proportions of ET prescription 24 months after surgery [95% confidence intervals (CIs)] were 0.088 [0.072, 0.11] in the non-adj-group and 0.058 [0.040, 0.084] in the adj-group. The cumulative proportion [95% CI] of women who received ET at 24 months after surgeries decreased with increasing age, ranging from 0.29 [0.21, 0.38] in the 40â44 years old to 0.009 [0.002, 0.034] in the 55â59 years old women in the non-adj-group and from 0.17 [0.094, 0.31] in the 40â44 years old to 0 in the 55â59 years old women in the adj-group. CONCLUSION: The present study shows that ET after endometrial cancer surgery may be underused, even in women who underwent surgery between 40 and 44 years of age and without adjuvant therapy.
Assuntos
População do Leste Asiático , Neoplasias do Endométrio , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Qualidade de Vida , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/cirurgia , Terapia de Reposição Hormonal , Estrogênios/uso terapêuticoRESUMO
BACKGROUND: Early identification of placental insufficiency can lead to appropriate treatment selections and can improve neonates' outcomes. Possible contributions of magnetic resonance imaging (MRI) have been suggested. PURPOSE: To evaluate the prognostic capabilities of placental intravoxel incoherent motion (IVIM) parameters and T2-relaxation time, and their correlation with fetal growth and adverse outcomes, comparing umbilical artery (UmA) pulsatility index (PI). MATERIAL AND METHODS: A total of 68 singleton pregnancies at 24-40 weeks of gestation underwent placental MRI and were reviewed retrospectively. UmA-PI was measured using Doppler ultrasound by obstetricians. IVIM parameters (Dfast, Dslow, and f) were calculated with a Bayesian model fitting. First, the associations between gestational age (GA) with placental IVIM parameters, T2-relaxation time, and placental thickness (PT) were evaluated. Second, IVIM parameters, T2 value (Z-score), PT (Z-score), and UmA-PI (Z-score) were compared between ( 1) those delivering small for gestational age (SGA) and appropriate for gestational age (AGA) neonates, ( 2) emergency cesarean section (ECS), and non-ECS, and ( 3) preterm birth and full-term birth. RESULTS: Low birth weight was observed in 15/68 cases (22%). GA was significantly associated only with T2-relaxation time and PT. SGA was significantly associated with T2 value (Z-score), f, and UmA-PI (Z-score). In the ECS groups, T2 value (Z-score), f, and Dfast were significantly lower than those in non-ECS groups. All IVIM parameters and T2 values (Z-score) showed significantly lower scores in the preterm birth group. CONCLUSION: Placental f and T2 value (Z-score) had significant associations with low birth weight and clinical adverse outcomes and could be potential imaging biomarkers of placental insufficiency.
Assuntos
Insuficiência Placentária , Nascimento Prematuro , Gravidez , Recém-Nascido , Humanos , Feminino , Placenta/diagnóstico por imagem , Insuficiência Placentária/diagnóstico por imagem , Estudos Retrospectivos , Artérias Umbilicais/diagnóstico por imagem , Teorema de Bayes , Cesárea , Imageamento por Ressonância Magnética/métodos , Movimento (Física) , Ultrassonografia Doppler , Imagem de Difusão por Ressonância MagnéticaRESUMO
AIM: Chronic abruption-oligohydramnios sequence (CAOS), which is characterized by vaginal bleeding and oligohydramnios, adversely affects the lungs of fetuses due to bloody amniotic fluid and oligohydramnios. The criteria for termination of pregnancy remain controversial. This study aimed to examine respiratory function in infants within 3 years after birth and risk factors for respiratory prognosis, and to clarify the management of CAOS. METHODS: This study is a case series of patients with CAOS managed at our institution between 2010 and 2020. The clinical data of the patients and their infants within 3 years after birth were reviewed. The amniotic fluid volume was measured using the maximum vertical pocket (MVP). RESULTS: Six of 17 neonates (35.3%) used inhaled nitric oxide (iNO) to improve oxygenation. Women with longer periods of MVP <1 cm delivered more neonates using iNO; however, periods of MVP <2 cm were not associated with iNO use. Almost half of the infants required home oxygen therapy when discharged, regardless of amniotic fluid volume. At 18 months corrected age, only one child needed respiratory support, and the others discontinued. Two neonates, both born at 23 weeks of gestational age, died within 1 month after birth because of extremely preterm birth. CONCLUSIONS: The amniotic fluid volume could predict the use of iNO in neonates, but it did not affect the child's respiratory function after the newborn period. Almost all children born to women with CAOS can improve their respiratory function as they grow up.