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Whether the association between metabolic syndrome (MetS) and functional disability differs depending on sex or age remains unknown. To determine the association between MetS and functional disability in older people separately by sex and age groups. A total of 11 083 participants (4407 men and 6676 women) aged 65 years or over without functional disability were enrolled. MetS was defined according to the revised NCEP ATP III guidelines. Functional disability was defined by a new certification in the long-term care insurance in Japan. Cox proportional hazards models were used to assess the risk of functional disability with adjustment for possible confounding factors. Over the mean observation period of 10.5 years, 1282 men and 2162 women experienced functional disability. For those aged 65 to 74 years, HRs (95% CIs) for functional disability in the MetS group were 1.33 (1.07-1.66) in men and 1.15 (1.000-1.32) in women. For those aged 75 years or older, there was no significant association in men or women. In subjects with a severe care need level, there was a marginal significant association in men aged 65 to 74 years. Among the MetS components that independently increased the risk of functional disability were glucose intolerance and elevated blood pressure (men and women aged 65-74 years), obesity (women aged 65-74 years), and glucose intolerance (women aged 75 years or older). MetS contributed to an increase in a high risk of future functional disability among individuals aged 65 to 74 years. In this age group, improvement of lifestyle, health promotion and interventions for MetS from middle age may prevent future functional disability.
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Pessoas com Deficiência , Síndrome Metabólica , Humanos , Síndrome Metabólica/epidemiologia , Idoso , Feminino , Masculino , Japão/epidemiologia , Fatores Sexuais , Pessoas com Deficiência/estatística & dados numéricos , Fatores Etários , Idoso de 80 Anos ou mais , Fatores de Risco , Modelos de Riscos Proporcionais , População do Leste AsiáticoRESUMO
OBJECTIVE: This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer. METHODS: This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival. RESULTS: Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months. CONCLUSION: Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.
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This case report highlights the need for clinicians to monitor patients with rhabdomyosarcoma for pancreatic metastasis to ensure that proper treatment is quickly provided, thereby improving outcomes.
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Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16-0.77]), all-comers (n = 57; 0.45 [0.22-0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12-1.07]). HRs (95% CI) for OS were 0.38 (0.14-1.01), 0.41 (0.17-1.00), and 0.37 (0.10-1.30), respectively. Incidence of grade 3-5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares , Neoplasias do Colo do Útero , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1 , Bevacizumab/uso terapêutico , Japão/epidemiologia , Neoplasias Pulmonares/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/etiologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
Ovarian cancer has the worst prognosis among gynecological cancers. In particular, clear cell and mucinous carcinomas are less sensitive to chemotherapy. The establishment of new therapies is necessary to improve the treatment outcomes for these carcinomas. In previous clinical studies, chemotherapy with cytotoxic anticancer drugs has failed to demonstrate better treatment outcomes than paclitaxel + carboplatin therapy. In recent years, attention has been focused on treatment with molecular target drugs and immune checkpoint inhibitors that target newly identified biomarkers. The issues that need to be addressed include the most appropriate combination of therapies, identifying patients who may benefit from each therapy, and how results should be incorporated into the standard of care for ovarian clear cell and mucinous carcinomas. In this article, we have reviewed the most promising therapies for ovarian clear cell and mucinous carcinomas, which are regarded as intractable, with an emphasis on therapies currently being investigated in clinical studies.
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OBJECTIVE: The primary objective of this study was to evaluate the safety of niraparib 300 mg/day in Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting. METHODS: Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients with platinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30 days after initial niraparib administration) was justified by the incidences of a global pivotal phase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematological adverse event of niraparib. The overall safety analysis examined other treatment-emergent adverse events (TEAEs). RESULTS: Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8-79.1) kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib 300 mg/day but this decreased in subsequent cycles (mean±standard deviation dose intensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. No progression-free or overall survival events occurred; only 1 of 4 response-evaluable patients had a post-baseline tumor assessment (stable disease). CONCLUSION: The incidence of grade 3 or 4 thrombocytopenia-related events in Japanese ovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall, the safety profile was acceptable and consistent with the known safety profile and previous experience with niraparib. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.
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Quimioterapia de Manutenção , Neoplasias Ovarianas , Feminino , Humanos , Indazóis , Japão/epidemiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , PiperidinasRESUMO
Ovarian clear cell carcinoma (OCCC) is a rare subtype of gynecological cancer for which well-characterized and authenticated model systems are scarce. We provide an extensive characterization of '105C', a cell line generated from an adenocarcinoma of the clear cell histotype using targeted next-generation sequencing, cytogenetic microarrays, along with analyses of AKT/mTOR signaling. We report that that the 105C cell line is a bona fide OCCC cell line, carrying PIK3CA, PTEN, and ARID1A gene mutations, consistent with OCCC, yet maintain a stable genome as reflected by low copy number variation. Unlike KOC-7c, TOV-21G, and RMG-V OCCC lines also mutated for the above genes, the 105C cells do not carry mutations in mismatch repair genes. Importantly, we show that 105C cells exhibit greater resistance to mTOR inhibition and carboplatin treatment compared to 9 other OCCC cell lines in 3D spheroid cultures. This resistance may be attributed to 105C cells remaining dormant in suspension culture which surprisingly, contrasts with several other OCCC lines which continue to proliferate in long-term suspension culture. 105C cells survive xenotransplantation but do not proliferate and metastasize. Collectively, we show that the 105C OCCC cell line exhibits unique properties useful for the pre-clinical investigation of OCCC pathobiology.
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Antineoplásicos/uso terapêutico , Instabilidade Genômica , Mutação/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Esferoides Celulares/patologia , Animais , Antineoplásicos/farmacologia , Adesão Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromossomos Humanos/genética , Variações do Número de Cópias de DNA/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genoma Humano , Instabilidade Genômica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Taxa de Mutação , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The molecular mechanisms responsible for the progression of ovarian cancer remain incompletely understood. By targeting multiple cancer-related genes, microRNAs (miRNAs) have been identified as key regulators of cancer development and progression. In addition, the microenvironment, which constitutes cancer glands and the surrounding stromal tissue at the invasive front, has an important role in cancer progression. Using array-based analysis of 14 cases (cohort 1), the aim of the present study was to evaluate global miRNA expression in cancerous glands and surrounding stromal tissues (isolated using a crypt isolation method), in order to identify potential prognostic markers of high-grade serous carcinoma (HGSC). Reverse transcription-quantitative PCR was also used to verify the results in cohort 1 (14 cases) and in 16 additional HGSC cases (cohort 2; verification cohort). Firstly, miRNA expression levels were compared between HGSC and normal samples among both the isolated cancer gland and stromal tissue samples. Secondly, miRNA expression was compared between HGSC cases with recurrence and those without recurrence among the isolated cancer gland and stromal tissue samples. The results revealed six and seven miRNAs identified in both of the aforementioned comparisons in isolated cancer glands and surrounding stromal tissue, respectively. Furthermore, downregulation of miRNA-214-3p in isolated cancer glands and downregulation of miRNA-320c in the corresponding stromal tissue were associated with a decrease in disease-free survival (without recurrence) in cohort 2. These findings indicated that specific miRNAs expressed in cancer cells and surrounding stromal cells of HGSC may be potential biomarkers predicting patient prognosis.
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INTRODUCTION: We report a rare case of renal cell carcinoma with vaginal metastasis that recurred with rapid progression and was resistant to sunitinib and nivolumab. CASE PRESENTATION: A 68-year-old woman presented with renal cell carcinoma and vaginal metastasis. Multiple lung metastasis appeared 3 months after simultaneous radical nephrectomy and hysterectomy with vaginal resection. Despite the treatment with sunitinib and nivolumab, the patient died 7 months after surgery. Immunohistochemical staining of primary and metastatic tumor specimens was CD8 and programmed death ligand-1 negative. CONCLUSION: Although vaginal metastasis of renal cell carcinoma is rare, lack of CD8 and programmed death ligand-1 expression may cause nivolumab resistance and may be useful markers in patients with metastatic renal cell carcinoma.
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Forchlorfenuron (FCF) is a synthetic plant cytokinin widely used in agriculture to promote fruit size, that paradoxically inhibits proliferation, migration, and invasion in human cancer cell lines. FCF has also been shown to affect HIF-1α and HER2, which are both known to play a crucial role in cancer cell survival. In this study, we have developed potent FCF analogs through structural modification of FCF, coined UR214-1, UR214-7, and UR214-9. Compared to parental FCF, these analogs are more effective in decreasing viability and proliferation in both ovarian and endometrial cancer cell lines. These FCF analogs also suppress HER2 expression at a concentration lower than that of FCF. In addition, we found that treatment with either FCF or its analogs decreases the expression of human epididymis protein 4 (HE4), which is commonly upregulated in ovarian and endometrial cancers. Given the association between cancer behavior and HE4 production in gynecologic cancers, our findings may provide insight useful in the development of new treatment strategies for gynecologic cancers.
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Desenvolvimento de Medicamentos , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Piridinas/química , Piridinas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Ovarianas/patologia , Receptor ErbB-2/metabolismo , Septinas/genética , Septinas/metabolismo , Taxa de Sobrevida , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/metabolismoRESUMO
BACKGROUND/AIM: Treatments for controlling delayed nausea after chemotherapy are inadequate, potentially inciting malnutrition. We sought to determine the incidence of nausea, anorexia, and food intake after chemotherapy. PATIENTS AND METHODS: Subjects were females with gynecological cancers who underwent chemotherapy between 2008 and 2013. Nausea, anorexia, and food intake in the acute (day 1) and delayed phases (days 2 and 3) were retrospectively evaluated. RESULTS: Subjects included 156 females. Chemotherapies were highly (HEC; n=24) and moderately emetogenic (MEC; n=132). There were no significant between-group differences for anorexia control during either the acute or the delayed phase and both groups demonstrated significantly worse control of nausea during the delayed phase. In the HEC group, food intake was significantly reduced on days 2 and 3 compared with day 1. CONCLUSION: Rates of nausea, anorexia, and food intake significantly worsened over time, particularly in the MEC group. Current supportive therapies appear inadequate and should be improved.
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Anorexia/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Ingestão de Alimentos , Neoplasias dos Genitais Femininos/tratamento farmacológico , Adulto , Idoso , Anorexia/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Neoplasias dos Genitais Femininos/complicações , Neoplasias dos Genitais Femininos/epidemiologia , Neoplasias dos Genitais Femininos/patologia , Humanos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Náusea/epidemiologia , Náusea/patologia , Vômito/induzido quimicamente , Vômito/epidemiologia , Vômito/patologiaRESUMO
BACKGROUND: Ovarian Sertoli-Leydig cell tumors (SLCTs) with androgenic manifestations harbor DICER1 mutations in 30-60% of cases. Ovarian SLCTs without DICER1 hotspot mutations have been reported to exhibit elderly onset and no androgenic manifestations. We present the first case of a primary mesenteric SLCT without DICER1 hotspot mutation. CASE PRESENTATION: An 84-year-old woman presented with a 75-mm mesenteric solid tumor. She presented no androgenic or estrogenic manifestations. She underwent ileocecal resection. Histologically, her mesenteric tumor showed histopathological features that resembled moderately differentiated SLCT. Moreover, DICER1 hotspot mutation was not detected. CONCLUSIONS: We described the first case of heterotopic primary mesenteric SLCT without DICER1 hotspot mutation.
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Neoplasias Ovarianas/diagnóstico , Tumor de Células de Sertoli-Leydig/diagnóstico , Idoso de 80 Anos ou mais , RNA Helicases DEAD-box , Feminino , Humanos , Mutação , Neoplasias Ovarianas/patologia , Ribonuclease III , Tumor de Células de Sertoli-Leydig/patologiaRESUMO
Oncolytic vaccinia virus (OVV) has demonstrated appropriate safety profiles for clinical development. Although designed to kill cancer cells efficiently, OVV sensitivity varies in individual cancers, and predictive biomarkers of therapeutic responses have not been identified. Here we found that OVV was much more efficient in KFTX paclitaxel-resistant ovarian cancer cells compared to that in KFlow paclitaxel-sensitive cells. Microarray analysis identified long non-coding RNA urothelial carcinoma-associated 1 (UCA1) upregulation, which contributed to both enhanced paclitaxel resistance and OVV spread. In addition, UCA1 expression correlated with efficient OVV spread in other ovarian cell lines and primary cancer cell cultures. When host pathways underlying OVV spread were analyzed, differences were detected in the activation of the Rho GTPase Cdc42, suggesting that filopodia formation enhances OVV cell-to-cell spread and tumor migration. Moreover, we established a clinically relevant mouse model of peritoneal metastasis using KFTX or KFlow cells. Paclitaxel exerted anti-tumor effects on KFlow, but not KFTX, tumors. In mice bearing KFTX cells after paclitaxel failure, OVV treatment induced the regression of residual tumors and improved survival. Our findings demonstrated that UCA1 promotes OVV cell-to-cell spread in ovarian cancer, resulting in enhanced therapeutic outcome.
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OBJECTIVE: Uterine carcinosarcoma (UCS) is a highly aggressive neoplasm that is composed of an intricate admixture of carcinomatous and sarcomatous elements. The relationship between UCS and the epithelial to mesenchymal transition (EMT) has been reported. In this study, we examined how expression of E-cadherin was associated with the expression of EMT-related proteins in UCS. METHODS: UCS samples were histologically divided into three components: carcinomatous, transitional, and sarcomatous regions. Next, we examined the expression of E-cadherin and EMT-related proteins, including SNAI2, ZEB1, and TWIST1, in each component of the UCS using immunohistochemistry. The expression score was determined by combining the staining intensity and staining area of the target cells. RESULTS: The expression score of E-cadherin was significantly lower in transitional and sarcomatous components than in the carcinomatous component. In addition, a significant difference in the low expression score of E-cadherin between transitional and sarcomatous components (transitional > sarcomatous components) was found. There were significant differences between the expression scores of ZEB1 in the three components (sarcomatous > transitional > carcinomatous components). However, no difference in the expression of TWIST1 between the components was found. Conversely, the expression level of SNAI2 was higher in sarcomatous or transitional components than in the carcinomatous component. However, a significant difference between the transitional and sarcomatous components was not detected. CONCLUSION: These results suggest that the EMT plays an essential role in the pathogenesis of UCS.
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BACKGROUND: We present the study rationale and design of the JGOG3023 study, an open-label, parallel-arm, randomized, phase II trial that aimed to assess the efficacy and safety of chemotherapy with or without bevacizumab in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who were previously treated with bevacizumab for front-line or platinum-sensitive ovarian cancer. We hypothesize that patients treated with a combination of single-agent chemotherapy and bevacizumab will show improved progression-free survival (PFS) compared with those treated with single-agent chemotherapy alone, in the setting beyond disease progression following prior bevacizumab treatment. METHODS/DESIGN: A total of 106 patients who have recurrence or progression of ovarian cancer, while receiving chemotherapy or within 6 months after the final dose of platinum, after completing at least three cycles of bevacizumab plus platinum chemotherapy will be randomized in a 1:1 ratio to treatment with single-agent chemotherapy or single-agent chemotherapy combined with bevacizumab. For chemotherapy, one of the following four drugs will be chosen by an investigator: pegylated liposomal doxorubicin, topotecan, paclitaxel, or gemcitabine. The primary endpoint is investigator-assessed PFS. The secondary endpoints are overall survival, objective response rate, number of paracentesis, and response rate by CA125. Safety will be evaluated by the incidence of adverse events. DISCUSSION: This study will assess the efficacy and safety of bevacizumab in combination with single-agent chemotherapy, which could be used continuously after disease progression following standard platinum-based chemotherapy with bevacizumab. TRIAL REGISTRATION: UMIN000017247 (registered April 22, 2015).
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Antineoplásicos , Bevacizumab , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Neoplasias Peritoneais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/mortalidade , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/mortalidade , Platina/efeitos adversos , Platina/uso terapêutico , Intervalo Livre de ProgressãoRESUMO
Recent studies have shown that cancer-associated fibroblasts (CAFs) and the epithelial-mesenchymal transition (EMT) contribute to invasive and metastatic abilities of ovarian cancer (OC) cells. In the present study, we attempted to identify the role of CAF- and EMT-related proteins in OCs, including serous carcinoma, mucinous carcinoma, endometrioid carcinoma and clear cell carcinoma using an immunohistochemical approach. The following CAF-related markers were used: CD10, podoplanin, fibroblast activating protein (FAP), platelet derived growth factor receptor (PDGFRα), PDGFRß, S100A4 and α-smooth muscle actin (α-SMA). In addition, the following EMT-related markers were investigated: Slug, TWIST1 and ZEB1We performed hierarchical cluster analysis to group the samples according to their scoring. Subgroup 1 was characterized by high expression of CD10, podoplanin, α-SMA, Slug and ZEB1, whereas subgroup 2 was closely associated with high expression of podoplanin, PDGFRα, PDGFRß, α-SMA, and Slug. In addition, marked expression of CD10 was observed in subgroup 3. High expression of α-SMA was a distinctive feature in subgroup 4, and expression of podoplanin and α-SMA characterized subgroup 5. Each subgroup was correlated with a histological type. The fact that different histological types were associated with different subgroups suggests the presence of distinct and heterogeneous subpopulations of CAFs in OC.
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Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome-centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells. Importantly, small molecule inhibitors of the BET (bromodomain and extra terminal domain) family of proteins, to which BRD2 belongs, specifically inhibit proliferation of ARID1A mutated cell lines, both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. BET inhibitors cause a reduction in the expression of multiple SWI/SNF members including ARID1B, providing a potential explanation for the observed lethal interaction with ARID1A loss. Our data indicate that BET inhibition may represent a novel treatment strategy for a subset of ARID1A mutated ovarian clear cell carcinomas.
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Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Mutação/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas/antagonistas & inibidores , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Feminino , Humanos , Camundongos , Ovário/efeitos dos fármacosRESUMO
Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient-derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models.Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928-40. ©2018 AACR.
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Adenocarcinoma de Células Claras/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Neoplasias Ovarianas/genética , Adenocarcinoma de Células Claras/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Morfolinas/farmacologia , Mutação/genética , Proteínas Nucleares/genética , Neoplasias Ovarianas/patologia , Transdução de Sinais/genética , Fatores de Transcrição/genéticaRESUMO
Purpose: To define the median endometrial thickness (ET) in office gynecology is thought to be important for clinical practice. However, there are few reports about ET that have included the general female population on a large scale. The median ET was determined prospectively in premenopausal women who attended office gynecology for cervical cancer screening. Methods: In total, 849 women were enrolled. The median ET was determined by using transvaginal ultrasound and the relationships between the ET and various clinical factors were analyzed. Results: The participants' median age was 38.5 years. The median ET was 8.6 mm (90% and 95% quantiles: 13.8 and 15.8 mm). The ET was not related to their age, symptoms, obstetric history, geographical location, or risk factors for endometrial cancer. In the women with a menstrual cycle length of 28-30 days, the ET was 7 mm on days 1-6, but it increased from 5.4 mm immediately after menstruation (day 7 or 8) to 9.2 mm on days 13-14. Subsequently, the ET increased further to 11.1 mm on day 18. Conclusion: In all the women, the upper limit of the ET was 13.8 mm and 15.8 mm in the 90% and 95% quantile, respectively, in office gynecology.