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To PARPI or Not to PARPI BRCA Mutated Ovarian Cancer Following First-line Chemotherapy, That is the Question? 一线化疗后 BRCA 基因突变卵巢癌要不要 PARPI?
Pub Date : 2021-01-01 Epub Date: 2021-08-03
Peter G Rose, Laura M Chambers, Michelle Kuznicki
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引用次数: 0
The Overtreatment and Cost Effectiveness of Primary versus Secondary Maintenance Therapy with Poly-Adenosine Ribose Phosphate Inhibitors (PARPi) for Epithelial Ovarian Cancer (EOC). 上皮性卵巢癌(EOC)的多腺苷核糖磷酸抑制剂(PARPi)一级与二级维持治疗的过度治疗和成本效益。
Pub Date : 2021-01-01 Epub Date: 2021-10-07
Peter G Rose, Meng Yao, Laura M Chambers, Lin Mei, Phuc Le

Background: No data exist to suggest PARP inhibitor (PARPi) therapy as first-line maintenance is superior to PARPi therapy as second-line maintenance.

Objective: To determine the efficacy and cost of primary versus secondary olaparib or niraparib maintenance in Epithelial Ovarian Cancer (EOC).

Methods: A retrospective cohort study was performed in women with EOC to determine the survival following primary or secondary PARPi maintenance. We modeled the costs of olaparib and niraparib based on previously published costs and duration of therapy based on the Solo 1/Solo 2 and Prima and Nova trials, respectively.

Results: Among 40 patients treated with PARPi as primary or secondary maintenance there was no difference in overall survival (p=0.97). Among 166 women with stage III/IV germ-line BRCA mutated EOC, 28.8% were disease free for >3 years (18.6% never recurred and 10.2% recurred >3 years after chemotherapy). Since 29% of the BRCA mutated patients did not recur within 3 years, primary olaparib maintenance therapy was significantly more expensive than secondary olaparib maintenance therapy by 260%. Primary niraparib maintenance therapy was slightly more expensive than secondary niraparib maintenance therapy by 4%, 51%, and 15% for BRCA mutated, HR deficient, and HR proficient patients, respectively. By eliminating the overtreatment of patients with primary PARPi therapy, the cost savings for 100 women with EOC with BRCA mutations would be $37,335,360 for olaparib and $8,197,592 for niraparib.

Conclusion: Up to 29% of BRCA mutated patients may be overtreated with primary PARPi maintenance with significantly increased treatment costs.

背景:没有数据表明PARP抑制剂(PARPi)治疗作为一线维持优于PARPi治疗作为二线维持。目的:确定原发性和继发性奥拉帕尼或尼拉帕尼维持治疗上皮性卵巢癌(EOC)的疗效和成本。方法:对EOC女性患者进行回顾性队列研究,以确定原发性或继发性PARPi维持后的生存率。我们分别基于先前发表的基于Solo 1/Solo 2和Prima和Nova试验的成本和治疗持续时间对olaparib和niraparib的成本进行了建模。结果:在40例以PARPi作为主要或次要维持治疗的患者中,总生存期无差异(p=0.97)。在166名III/IV期生殖系BRCA突变EOC的女性中,28.8%的患者在化疗后3年以上无疾病(18.6%从未复发,10.2%在化疗后3年以上复发)。由于29%的BRCA突变患者在3年内没有复发,因此初级奥拉帕尼维持治疗的费用明显高于二级奥拉帕尼维持治疗的260%。BRCA突变、HR缺陷和HR熟练患者的初级尼拉帕尼维持治疗分别比次级尼拉帕尼维持治疗贵4%、51%和15%。通过消除原发性PARPi治疗患者的过度治疗,100名携带BRCA突变的EOC女性患者使用奥拉帕尼可节省37,335,360美元,使用尼拉帕尼可节省8,197,592美元。结论:高达29%的BRCA突变患者可能会过度接受初级PARPi维持治疗,从而显著增加治疗费用。
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引用次数: 0
Chemotherapy for Elderly Ovarian Cancer Patients 老年卵巢癌患者的化疗
Pub Date : 2016-08-01 DOI: 10.4172/2161-0932.1000397
Sivraj Muralikrishnan, C. Hatzis, A. Katz, A. Santin, P. Schwartz, M. Abu-Khalaf
Objective Ovarian cancer is the most lethal cancer involving the female pelvic reproductive system. Its incidence increases with age and with an aging population, its prevalence should also increase. The goal of our retrospective study is to report our experience in treating women over 65 years of age, with a diagnosis of primary ovarian cancer, using standard intravenous chemotherapy. Methods The medical records of 78 patients>65 years of age diagnosed with primary ovarian cancer at the Yale Cancer Center between 1996–2006 were retrospectively reviewed and included in our analysis. Patients had stage I–IV disease (stage I n=5, stage II n=8, stage III n=36, stage IV n=25, unknown n=4). Results Sixty-three of 78 women (80.8%) completed the prescribed regimen; and 62 women did not require a dose reduction or chemotherapy discontinuation. The most common reason for a dose reduction or treatment discontinuation was fatigue (6.4%), neutropenia (2.6%), patient preference (2.6%), and multiple co-morbidities (2.6%). The most commonly used regimen was paclitaxel 175mg/m2 and carboplatin AUC 5. The hazard ratio for PFS and OS for patients who had dose reduction/discontinuation versus those who completed the prescribed dose was 1.3 (95% CI 0.51–3.26) and 0.63 (95% CI 0.17–2.33), respectively. Conclusions Our findings illustrate that elderly women are able to tolerate standard chemotherapy with relatively few significant adverse effects. While different treatment modalities in ovarian cancer are continually being evaluated, additional prospective studies are required to better understand the tolerability and efficacy of such treatment in the elderly population.
目的卵巢癌是女性盆腔生殖系统最致命的恶性肿瘤。其发病率随着年龄的增长而增加,随着人口老龄化,其患病率也应增加。我们回顾性研究的目的是报告我们使用标准静脉化疗治疗65岁以上诊断为原发性卵巢癌的女性的经验。方法回顾性分析1996-2006年耶鲁大学癌症中心收治的78例年龄>65岁的原发性卵巢癌患者的病历资料。患者为I - IV期疾病(I期5例,II期8例,III期36例,IV期25例,未知4例)。结果78例妇女中63例(80.8%)完成了规定的治疗方案;62名妇女不需要减少剂量或停止化疗。减少剂量或停止治疗的最常见原因是疲劳(6.4%)、中性粒细胞减少(2.6%)、患者偏好(2.6%)和多种合并症(2.6%)。最常用的方案是紫杉醇175mg/m2加卡铂AUC 5。减量/停药的患者与完成规定剂量的患者相比,PFS和OS的风险比分别为1.3 (95% CI 0.51-3.26)和0.63 (95% CI 0.17-2.33)。结论:我们的研究结果表明,老年妇女能够耐受标准化疗,相对较少的显著不良反应。虽然卵巢癌的不同治疗方式正在不断地被评估,但需要更多的前瞻性研究来更好地了解这种治疗在老年人群中的耐受性和疗效。
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引用次数: 6
Exosomes in Plasma of Patients with Ovarian Carcinoma: Potential Biomarkers of Tumor Progression and Response to Therapy. 卵巢癌患者血浆中的外泌体:肿瘤进展和治疗反应的潜在生物标志物。
Pub Date : 2013-04-29 DOI: 10.4172/2161-0932.S4-003
Marta Szajnik, Magdalena Derbis, Michal Lach, Paulina Patalas, Marcin Michalak, Hanna Drzewiecka, Dariusz Szpurek, Andrzej Nowakowski, Marek Spaczynski, Włodzimierz Baranowski, Theresa L Whiteside

Background: In patients with Ovarian Cancer (OvCa) exosomes released by tumor cells are present in the plasma and could be involved in tumor progression. This study examines the association between the exosome presence/protein content in plasma of OvCa patients and disease outcome, response to standard therapy and/or tumorresistance to therapies in patients studied at diagnosis and also serially during and after therapy.

Design and methods: Exosomes were purified from OvCa patients' plasma (n=22), patients with benign tumors (n=10) or (n=10) healthy controls (NC) using ultracentrifugation. Exosomes were visualized by scanning electron microscopy. Their protein content was measured. The presence of MAGE 3/6 and TGF-β1 in exosomes was evaluated in Western blots.

Results: The OvCa patients' plasma contained higher levels of exosomal proteins (p<0.05) compared to those isolated from plasma of patients with benign tumors or NC. Exosomes isolated from OvCa patients's plasma carried TGF-β1 and MAGE3/6, which distinguished OvCa patients from those with benign tumors and NC. High protein levels of exosomes were seen in newly diagnosed patients; however in advanced stages of OvCa patients the protein content of isolated exosomes was significantly higher than that of early stages. The exosome levels variably changed during/after chemotherapy, and correlations between the changes in exosomal protein levels and clinical data suggested that the protein content of exosomes might be useful in predicting responses to therapy and prognosis in OvCa patients.

Conclusion: Analysis of plasma exosomes levels offers a novel approach to diagnosis and monitoring response to therapies in OvCa patients.

背景:在卵巢癌(OvCa)患者中,肿瘤细胞释放的外泌体存在于血浆中,并可能参与肿瘤的进展。本研究探讨了OvCa患者血浆中外泌体存在/蛋白质含量与疾病结局、对标准治疗的反应和/或患者在诊断时以及治疗期间和治疗后对治疗的肿瘤耐药性之间的关系。设计和方法:采用超离心技术从OvCa患者(n=22)、良性肿瘤患者(n=10)和健康对照(n=10)的血浆中纯化外泌体。扫描电镜观察外泌体。测定其蛋白质含量。Western blot检测外泌体中MAGE 3/6和TGF-β1的表达。结果:OvCa患者血浆中外泌体蛋白含量较高(结论:分析血浆外泌体水平为OvCa患者的诊断和治疗反应监测提供了一种新的方法。
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引用次数: 171
Maternal Hypothyroidism and Pregnancy Loss: Awaiting Firm Recommendations on Testing and Treatment. 母亲甲状腺功能减退和妊娠丢失:等待测试和治疗的坚定建议。
Pub Date : 2013-02-01 DOI: 10.4172/2161-0932.1000142
Jennifer Lovegreen, Danny J Schust
Since up to 75% of fertilized ova and at least 15% of clinicallyrecognized pregnancies do not survive to birth, spontaneous loss is the most common complication of human pregnancy. The majority of pregnancy losses occur prior to clinical detection. Set against this startlingly high background, spontaneous loss of two pregnancies occurs in approximately 1% of pregnancies and loss of three or more pregnancies in 1 in 300 couples. Although isolated fetal aneuploidy is certainly etiologic in many pre-clinical and clinical losses, other causes have been suggested. In the last 15 years, there has been an increasing interest in the role of thyroid dysfunction and in thyroid autoimmunity in patients with pregnancy wastage and many clinicians have instituted thyroid-related testing and treatment protocols based on this growing body of literature. It is important to re-examine the evidence for these interventions and to consider risk: benefit balances in acting on the existing literature. The physiologic and metabolic demands of pregnancy require increased production of thyroid hormone from the maternal gland and the positive linear relationship reported between maternal TSH levels and pregnancy loss [1] suggests that inadequate response to these demands may be problematic. It might follow that thyroid hormone supplementation for those women who may suffer adverse alterations in thyroid function during pregnancy may help to avert pregnancy loss. Several questions immediately arise, including: 1) Which women should be screened and 2) At what TSH levels should supplementation be recommended. This topic was systematically reviewed within the past 12 months and the meta-analysis presented indicated that use of levothyroxine to treat clinical hypothyroidism significantly decreased pregnancy loss rates (RR: 0.19; CI: 0.08-0.39) [2]. The same study could not definitively determine whether treatment of subclinical hypothyroidism improves pregnancy maintenance [2]. Note that the investigators in this study collected well over 7000 relevant articles for consideration but only 11 could be included in their meta-analysis. Like much of the other literature in the pregnancy loss field, there is a dearth of well-designed investigations on this topic. The same Dutch group published another meta-analysis about a year prior that addressed the effects of subclinical hypothyroidism on pregnancy maintenance and found a positive association with perinatal mortality (OR 2.7; 95% CI: 1.6-4.7) [3]. They also extended this investigation to include an assessment of the effects of thyroid auto antibodies on adverse pregnancy outcomes and found a positive relationship between the presence of anti-Thyroglobulin (anti-TG) and anti-Thyroidperoxidase (anti-TPO) antibodies and isolated (OR 3.7; 95% CI: 1.8-7.6) and recurrent (OR 2.3; 95% CI: 1.5-3.5) pregnancy loss [3]. This latter study did not address treatment paradigms, but again only a very small proportion of the existing literature
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引用次数: 1
Re-examining Sonographic Cut-off Values for Diagnosing Early Pregnancy Loss. 超声切断值诊断早期妊娠丢失的再研究。
Pub Date : 2013-01-01 DOI: 10.4172/2161-0932.1000141
Jennifer Bickhaus, Erin Perry, Danny J Schust
Early pregnancy loss is the most common complication of human pregnancy [1]. Such commonality requires dependable evaluation tools and informed, standardized criteria for accurate diagnosis. A brief perusal of the data on which most of the practitioners who treat women who are newly pregnant have based their recommendations for the sonographic diagnosis of a non-viable pregnancy raises significant concern since most of these data are based on relatively small patient numbers [2–5]. Further, recent studies have shown that the measurements used to determine historically-accepted criteria have fairly wide patient-to-patient, hyphenate intra-observer and interobserver variability [6]. This makes the inclusion of investigations based upon small patient numbers even more problematic. This unfortunate combination poses an important problem because the diagnosis of failed pregnancy has immense implications to the physical health of the mother and to the emotional well-being of the mother, her partner, her family and her close friends. The criteria for diagnosing a non-viable pregnancy must have a specificity that is as close to 100% as possible. Still, using commonly accepted historical sonographic criteria, authors have shown that between 1 in 100 and 4 in 100 viable pregnancies might be erroneously deemed non-viable [7,8]. If these incorrect diagnoses lead to immediate interventions, some pregnancies will be inadvertently terminated. Such outcomes are unacceptable. There should be near zero tolerance for misdiagnosis. Increased awareness of this too common problem has led to efforts to improve our diagnostic accuracy and has required a stringent re-evaluation of historical diagnostic criteria using investigations that include much larger study populations that have been evaluated using the most sensitive, commonly-available diagnostic modalities. In this case, the most sensitive ultrasonographic technique available for diagnosing an early, non-viable pregnancy is transvaginal sonography.
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引用次数: 8
Molecular Strategies of Deoxynucleotide Triphosphate Supply Inhibition Used in the Treatment of Gynecologic Malignancies. 抑制三磷酸脱氧核苷酸供应用于妇科恶性肿瘤治疗的分子策略。
Pub Date : 2011-12-10 DOI: 10.4172/2161-0932.s4-001
Charles A Kunos, Tomas Radivoyevitch

Chemotherapies targeting deoxynucleotide triphosphate synthesis are of high medical interest in the treatment of gynecologic malignancies. In this article, we focus on targeted inhibitors of ribonucleotide reductase, an enzyme in charge of ribonucleotide reduction to their corresponding deoxyribonucleotide to be used as the building blocks of DNA. We also discuss human clinical trials have utilized ribonucleotide reductase subunit-specific inhibitors, particularly trials for women with cervical cancer.

靶向三磷酸脱氧核苷酸合成的化疗在妇科恶性肿瘤的治疗中具有很高的医学意义。在本文中,我们重点关注核糖核苷酸还原酶的靶向抑制剂,核糖核苷酸还原酶是一种负责将核糖核苷酸还原为相应的脱氧核糖核苷酸以用作DNA构建块的酶。我们还讨论了利用核糖核苷酸还原酶亚基特异性抑制剂的人体临床试验,特别是宫颈癌妇女的试验。
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引用次数: 10
期刊
Gynecology & obstetrics (Sunnyvale, Calif.)
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