Evaluation of paraneoplastic antigens reveals TRIM21 autoantibodies as biomarker for early detection of ovarian cancer in combination with autoantibodies to NY-ESO-1 and TP53.
副肿瘤抗原的评价揭示 TRIM21 自身抗体作为卵巢癌早期检测的生物标志物，结合 NY-ESO-1 和 tp53 的自身抗体。
- 作者列表："Hurley LC","Levin NK","Chatterjee M","Coles J","Muszkat S","Howarth Z","Dyson G","Tainsky MA
BACKGROUND:The majority of ovarian cancer cases are diagnosed at an advanced stage with poor prognosis. This study evaluates autoantibodies against tumor antigens to identify candidate biomarkers for early detection of ovarian cancer in women at increased risk. OBJECTIVE:To assess the immunoreactivity of paraneoplastic antigens and tumor associated antigens with high-grade serous ovarian cancer (HGSOC) samples. METHODS:Five paraneoplastic antigens along with three tumor-associated antigens were evaluated with HGSOC patient serum samples. Validation screening was performed with n= 164 serum samples consisting of: 50 late stage HGSOC, 14 early stage HGSOC, 50 benign ovarian cyst, and 50 healthy control samples on ELISA and western blot. The four markers TRIM21, NY-ESO-1, TP53, and PAX8 were evaluated on a second validation serum set, n= 150. RESULTS:TRIM21 achieved the highest sensitivity in the first validation screening of 33% with 100% specificity. Combining TRIM21 with NY-ESO-1, TP53, and PAX8 provided 67% sensitivity with 94% specificity, and 56% sensitivity at 98% specificity. These four markers resulted in 46% sensitivity with 98% specificity in the second validation cohort; TRIM21 achieved the highest individual sensitivity of 36%. CONCLUSIONS:Autoantibodies to TRIM21, NY-ESO-1, and TP53 may complement CA125 in screening of women at genetic risk for ovarian cancer.
背景: 大多数卵巢癌病例诊断为晚期，预后较差。本研究评估针对肿瘤抗原的自身抗体，以确定风险增加的女性卵巢癌早期检测的候选生物标志物。 目的: 评估高级别浆液性卵巢癌 (HGSOC) 标本中副肿瘤抗原和肿瘤相关抗原的免疫反应性。 方法: 用 HGSOC 患者血清样本评价 5 种副肿瘤抗原和 3 种肿瘤相关抗原。用 n = 164 份血清样本进行验证筛选，包括: 50 份晚期 HGSOC 、 14 份早期 HGSOC 、 50 份良性卵巢囊肿和 50 份 ELISA 和 western blot 健康对照样本。在第二个验证血清集 (n = 150) 上评价了四种标志物 TRIM21 、 NY-ESO-1 、 TP53 和 PAX8。 结果: TRIM21 在首次验证筛查中达到最高的灵敏度为 33%，特异性为 100%。将 TRIM21 与 NY-ESO-1 、 TP53 和 PAX8 相结合，敏感性为 67%，特异性为 94%，敏感性为 56%，特异性为 98%。在第二个验证队列中，这四个标志物的敏感性为 46%，特异性为 98%; TRIM21 的个体敏感性最高，为 36%。 结论: 针对 TRIM21 、 NY-ESO-1 和 TP53 的自身抗体可能在筛查有卵巢癌遗传风险的女性中补充 CA125。
METHODS:STUDY OBJECTIVE:To evaluate the differences in perioperative outcomes and immediate complication rates between laparoscopic myomectomy for submucous myomas and laparoscopic myomectomy for myomas in other locations. DESIGN:Retrospective cohort study. SETTING:University-affiliated hospital in London. PATIENTS:A total of 350 patients with symptomatic uterine myomas underwent laparoscopic myomectomy. Thirty-three of these were performed for submucous myomas (group 1), and 317 were for myomas in other uterine locations (group 2). INTERVENTIONS:Analysis of prospectively collected data on patient demographics, myoma characteristics, perioperative outcomes, and immediate complications. MEASUREMENTS AND MAIN RESULTS:Patient demographics, including age, body mass index, and parity, were similar in the 2 groups. No significant differences in myoma characteristics were seen between groups 1 and 2, including the mean dimension of largest myoma (7.1 vs 7.8 cm, respectively; p = .35), mean number of myomas removed (3.8 vs 4.1; p = .665), and mean mass of myomas removed (142.0 g vs 227.3 g; p = .186). There were also no significant between-group differences in any perioperative outcomes, including mean blood loss (226.8 mL vs 266.4 mL; p = .373), duration of surgery (103 minutes vs 113 minutes; p = .264), and duration of hospital stay (1.4 days vs 1.7 days; p = .057). No complications arose from laparoscopic resection of submucous myomas. CONCLUSION:Laparoscopic myomectomy for submucous myomas has similar perioperative outcomes and immediate complications as laparoscopic myomectomy for other myomas and can be considered for large or type 2 submucous myomas.
METHODS:INTRODUCTION:Laparoscopic myomectomy can be difficult when fibroids are large and numerous. This may result in extensive intraoperative bleeding and the need for a conversion to a laparotomy. Medical pretreatment prior to surgery might reduce these risks by decreasing fibroid size and vascularization of the fibroid. We compared pretreatment with ulipristal acetate (UPA) vs gonadotropin-releasing hormone agonists (GnRHa) prior to laparoscopic myomectomy on several intra- and postoperative outcomes. MATERIAL AND METHODS:We performed a non-inferiority double-blind randomized controlled trial in nine hospitals in the Netherlands. Women were randomized between daily oral UPA for 12 weeks and single placebo injection or single intramuscular injection with leuprolide acetate and daily placebo tablets for 12 weeks. The primary outcome was intraoperative blood loss. Secondary outcomes were reduction of fibroid volume, suturing time, total surgery time and surgical ease. RESULTS:Thirty women received UPA and 25 women leuprolide acetate. Non-inferiority of UPA regarding intraoperative blood loss was not demonstrated. When pretreated with UPA, median intraoperative blood loss was statistically significantly higher (525 mL [348-1025] vs 280 mL[100-500]; P = 0.011) and suturing time of the first fibroid was statistically significantly longer (40 minutes [28-48] vs 22 minutes [14-33]; P = 0.003) compared with GnRHa. Pretreatment with UPA showed smaller reduction in fibroid volume preoperatively compared with GnRHa (-7.2% [-35.5 to 54.1] vs -38.4% [-71.5 to -19.3]; P = 0.001). Laparoscopic myomectomies in women pretreated with UPA were subjectively judged more difficult than in women pretreated with GnRHa. CONCLUSIONS:Non-inferiority of UPA in terms of intraoperative blood loss could not be established, possibly due to the preliminary termination of the study. Pretreatment with GnRHa was more favorable than UPA in terms of fibroid volume reduction, intraoperative blood loss, hemoglobin drop directly postoperatively, suturing time of the first fibroid and several subjective surgical ease parameters.
METHODS:AIMS:Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH-negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance. METHODS AND RESULTS:We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)-based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH-negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil-like cytoplasm. We found that six (86%) of seven FH-negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours. CONCLUSION:Our study showed a relatively high rate of FH germline mutation in FH-negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.